Spiro-oxindole compounds and their uses as therapeutic agents

ABSTRACT

This invention is directed to spiro-oxindole compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein k, j, Q, R 1,  R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 3c , and R 3d  are as defined herein, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, which are useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain. Pharmaceutical compositions comprising the compounds and methods of preparing and using the compounds are also disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/402,310, filed Apr. 11, 2006 (now allowed); which claims the benefitunder 37 U.S.C. §119(e) of U.S. Provisional Patent Application No.60/670,896 filed Apr. 11, 2005. These applications are incorporatedherein by reference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to spiro-oxindole compounds. Inparticular, this invention is directed to spiro-oxindole compounds thatare sodium channel blockers and are therefore useful in treating sodiumchannel-mediated diseases or conditions, such as pain, as well as otherdiseases and conditions associated with the mediation of sodiumchannels.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels, transmembrane proteins that initiateaction potentials in nerve, muscle and other electrically excitablecells, are a necessary component of normal sensation, emotions, thoughtsand movements (Catterall, W. A., Nature (2001), Vol. 409, pp. 988-990).These channels consist of a highly processed alpha subunit that isassociated with auxiliary beta subunits. The pore-forming alpha subunitis sufficient for channel function, but the kinetics and voltagedependence of channel gating are in part modified by the beta subunits(Goldin et al., Neuron (2000), Vol. 28, pp. 365-368). Each alpha-subunitcontains four homologous domains, Ito IV, each with six predictedtransmembrane segments. The alpha-subunit of the sodium channel, formingthe ion-conducting pore and containing the voltage sensors regulatingsodium ion conduction has a relative molecular mass of 260,000.Electrophysiological recording, biochemical purification, and molecularcloning have identified ten different sodium channel alpha subunits andfour beta subunits (Yu, F. H., et al., Sci. STKE (2004), 253; and Yu, F.H., et al., Neurosci. (2003), 20:7577-85).

The hallmarks of sodium channels include rapid activation andinactivation when the voltage across the plasma membrane of an excitablecell is depolarized (voltage-dependent gating), and efficient andselective conduction of sodium ions through conducting pores intrinsicto the structure of the protein (Sato, C., et al., Nature (2001),409:1047-1051). At negative or hyperpolarized membrane potentials,sodium channels are closed. Following membrane depolarization, sodiumchannels open rapidly and then inactivate. Channels only conductcurrents in the open state and, once inactivated, have to return to theresting state, favoured by membrane hyperpolarization, before they canreopen. Different sodium channel subtypes vary in the voltage range overwhich they activate and inactivate as well as their activation andinactivation kinetics.

The sodium channel family of proteins has been extensively studied andshown to be involved in a number of vital body functions. Research inthis area has identified variants of the alpha subunits that result inmajor changes in channel function and activities, which can ultimatelylead to major pathophysiological conditions. Implicit with function,this family of proteins are considered prime points of therapeuticintervention. Na_(v)1.1 and Na_(v)1.2 are highly expressed in the brain(Raymond, C. K., et al., J. Biol. Chem. (2004), 279(44):46234-41) andare vital to normal brain function. In humans, mutations in Na_(v)1.1and Na_(v)1.2 result in severe epileptic states and in some cases mentaldecline (Rhodes, T. H., et al., Proc. Natl. Acad. Sci. USA(2004),101(30):11147-52; Kamiya, K., et al., J. Biol. Chem. (2004),24(11):2690-8; Pereira, S., et al., Neurology (2004), 63(1):191-2). Assuch both channels have been considered as validated targets for thetreatment of epilepsy (see PCT Published Patent Publication No. WO01/38564). Na_(v)1.3 is broadly expressed throughout the body (Raymond,C. K., et al., op. cit.). It has been demonstrated to have itsexpression upregulated in the dorsal horn sensory neurons of rats afternervous system injury (Hains, B. D., et al., J. Neurosci. (2003),23(26):8881-92). Many experts in the field have considered Na_(v)1.3 asa suitable target for pain therapeutics (Lai, J., et al., Curr. Opin.Neurobiol. (2003), (3):291-72003; Wood, J. N., et al., J. Neurobiol.(2004), 61(1):55-71; Chung, J. M., et al., Novartis Found Symp. (2004),261:19-27; discussion 27-31, 47-54).

Na_(v)1.4 expression is essentially limited to muscle (Raymond, C. K.,et al., op. cit.). Mutations in this gene have been shown to haveprofound effects on muscle function including paralysis, (Tamaoka A.,Intern. Med. (2003), (9):769-70). Thus, this channel can be considered atarget for the treatment of abnormal muscle contractility, spasm orparalysis.

The cardiac sodium channel, Na_(v)1.5, is expressed mainly in the heartventricles and atria (Raymond, C. K., et al., op. cit.), and can befound in the sinovial node, ventricular node and possibly Purkinjecells. The rapid upstroke of the cardiac action potential and the rapidimpulse conduction through cardiac tissue is due to the opening ofNa_(v)1.5. As such, Na_(v)1.5 is central to the genesis of cardiacarrhythmias. Mutations in human Na_(v)1.5 result in multiple arrhythmicsyndromes, including, for example, long QT3 (LQT3), Brugada syndrome(BS), an inherited cardiac conduction defect, sudden unexpectednocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS)(Liu, H. et al., Am. J. Pharmacogenomics (2003), 3(3):173-9). Sodiumchannel blocker therapy has been used extensively in treating cardiacarrhythmias. The first antiarrhythmic drug, quinidine, discovered in1914, is classified as a sodium channel blocker.

Na_(v)1.6 encodes an abundant, widely distributed voltage-gated sodiumchannel found throughout the central and peripheral nervous systems,clustered in the nodes of Ranvier of neural axons (Caldwell, J. H., etal., Proc. Natl. Acad. Sci. USA (2000), 97(10): 5616-20). Although nomutations in humans have been detected, Na_(v)1.6 is thought to play arole in the manifestation of the symptoms associated with multiplesclerosis and has been considered as a target for the treatment of thisdisease (Craner, M. J., et al., Proc. Natl. Acad. Sci. USA (2004),101(21):8168-73).

Na_(v)1.7 was first cloned from the pheochromocytoma PC12 cell line(Toledo-Aral, J. J., et al., Proc. NatI.Acad. Sci. USA (1997),94:1527-1532). Its presence at high levels in the growth cones ofsmall-diameter neurons suggested that it could play a role in thetransmission of nociceptive information. Although this has beenchallenged by experts in the field as Na_(v)1.7 is also expressed inneuroendocrine cells associated with the autonomic system (Klugbauer,N., et al., EMBO J. (1995), 14(6):1084-90) and as such has beenimplicated in autonomic processes. The implicit role in autonomicfunctions was demonstrated with the generation of Na_(v)1.7 nullmutants; deleting Na_(v)1.7 in all sensory and sympathetic neuronsresulted in a lethal perinatal phenotype. (Nassar, et al., Proc. Natl.Acad. Sci. USA (2004), 101(34):12706-11.). In contrast, by deleting theNa_(v)1.7 expression in a subset of sensory neurons that arepredominantly nociceptive, a role in pain mechanisms, was demonstrated(Nassar, et al., op. cit.). Further support for Na_(v)1.7 blockersactive in a subset of neurons is supported by the finding that two humanheritable pain conditions, primary erythermalgia and familial rectalpain, have been shown to map to Na_(v)1.7 (Yang, Y., et al., J. Med.Genet. (2004), 41(3):171-4).

The expression of Na_(v)1.8 is essentially restricted to the DRG(Raymond, C. K., et al., op. cit.). There are no identified humanmutations for Na_(v)1.8. However, Na_(v)1.8-null mutant mice wereviable, fertile and normal in appearance. A pronounced analgesia tonoxious mechanical stimuli, small deficits in noxious thermoreceptionand delayed development of inflammatory hyperalgesia suggested to theresearchers that Na_(v)1.8 plays a major role in pain signalling(Akopian, A. N., et al., Nat. Neurosci. (1999), 2(6): 541-8). Blockingof this channel is widely accepted as a potential treatment for pain(Lai, J, et al., op. cit.; Wood, J. N., et al., op. cit.; Chung, J. M.,et al., op. cit.). PCT Published Patent Application No. WO03/037274A2describes pyrazole-amides and sulfonamides for the treatment of centralor peripheral nervous system conditions, particularly pain and chronicpain by blocking sodium channels associated with the onset or recurranceof the indicated conditions. PCT Published Patent Application No.WO03/037890A2 describes piperidines for the treatment of central orperipheral nervous system conditions, particularly pain and chronic painby blocking sodium channels associated with the onset or recurrence ofthe indicated conditions. The compounds, compositions and methods ofthese inventions are of particular use for treating neuropathic orinflammatory pain by the inhibition of ion flux through a channel thatincludes a PN3 (Na_(v)1.8) subunit.

The tetrodotoxin insensitive, peripheral sodium channel Na_(v)1.9,disclosed by Dib-Hajj, S. D., et al. (see Dib-Hajj, S. D., et al., Proc.Natl. Acad. Sci. USA (1998), 95(15):8963-8) was shown to reside solelyin the dorsal root ganglia. It has been demonstrated that Na_(v)1.9underlies neurotrophin (BDNF)-evoked depolarization and excitation, andis the only member of the voltage gated sodium channel superfamily to beshown to be ligand mediated (Blum, R., Kafitz, K. W., Konnerth, A.,Nature (2002), 419 (6908):687-93). The limited pattern of expression ofthis channel has made it a candidate target for the treatment of pain(Lai, J, et al., op. cit.; Wood, J. N., et al., op. cit.; Chung, J. M.et al., op. cit.).

NaX is a putative sodium channel, which has not been shown to be voltagegated. In addition to expression in the lung, heart, dorsal rootganglia, and Schwann cells of the peripheral nervous system, NaX isfound in neurons and ependymal cells in restricted areas of the CNS,particularly in the circumventricular organs, which are involved inbody-fluid homeostasis (Watanabe, E., et al., J. Neurosci. (2000),20(20):7743-51). NaX-null mice showed abnormal intakes of hypertonicsaline under both water- and salt-depleted conditions. These findingssuggest that the NaX plays an important role in the central sensing ofbody-fluid sodium level and regulation of salt intake behaviour. Itspattern of expression and function suggest it as a target for thetreatment of cystic fibrosis and other related salt regulating maladies.

Studies with the sodium channel blocker tetrodotoxin (TTX) used to lowerneuron activity in certain regions of the brain, indicate its potentialuse in the treatment of addiction. Drug-paired stimuli elicit drugcraving and relapse in addicts and drug-seeking behavior in rats. Thefunctional integrity of the basolateral amygdala (BLA) is necessary forreinstatement of cocaine-seeking behaviour elicited bycocaine-conditioned stimuli, but not by cocaine itself. BLA plays asimilar role in reinstatement of heroin-seeking behavior. TTX-inducedinactivation of the BLA on conditioned and heroin-primed reinstatementof extinguished heroin-seeking behaviour in a rat model (Fuchs, R. A.and See, R. E., Psychopharmacology (2002) 160(4):425-33).

This closely related family of proteins has long been recognised astargets for therapeutic intervention. Sodium channels are targeted by adiverse array of pharmacological agents. These include neurotoxins,antiarrhythmics, anticonvulsants and local anesthetics (Clare, J. J., etal., Drug Discovery Today (2000) 5:506-520). All of the currentpharmacological agents that act on sodium channels have receptor siteson the alpha subunits. At least six distinct receptor sites forneurotoxins and one receptor site for local anesthetics and relateddrugs have been identified (Cestèle, S. et al., Biochimie (2000), Vol.82, pp. 883-892).

The small molecule sodium channel blockers or the local anesthetics andrelated antiepileptic and antiarrhythmic drugs, interact withoverlapping receptor sites located in the inner cavity of the pore ofthe sodium channel (Catterall, W. A., Neuron (2000), 26:13-25). Aminoacid residues in the S6 segments from at least three of the four domainscontribute to this complex drug receptor site, with the IVS6 segmentplaying the dominant role. These regions are highly conserved and assuch most sodium channel blockers known to date interact with similarpotency with all channel subtypes. Nevertheless, it has been possible toproduce sodium channel blockers with therapeutic selectivity and asufficient therapeutic window for the treatment of epilepsy (e.g.lamotrignine, phenytoin and carbamazepine) and certain cardiacarrhythmias (e.g. lignocaine, tocainide and mexiletine). However, thepotency and therapeutic index of these blockers is not optimal and havelimited the usefulness of these compounds in a variety of therapeuticareas where a sodium channel blocker would be ideally suited.

Management of Acute and Chronic Pain

Drug therapy is the mainstay of management for acute and chronic pain inall age groups, including neonates, infants and children. The pain drugsare classified by the American Pain Society into three maincategories: 1) non-opioid analgesics-acetaminophen, and non-steroidalanti-inflammatory drugs (NSAIDs), including salicylates (e.g. aspirin),2) opioid analgesics and 3) co-analgesics.

Non-opioid analgesics such as acetaminophen and NSAIDs are useful foracute and chronic pain due to a variety of causes including surgery,trauma, arthritis and cancer. NSAIDs are indicated for pain involvinginflammation because acetaminophen lacks anti-inflammatory activity.Opioids also lack anti-inflammatory activity. All NSAIDs inhibit theenzyme cyclooxygenase (COX), thereby inhibiting prostaglandin synthesisand reducing the inflammatory pain response. There are at least two COXisoforms, COX-1 and COX-2. Common non-selective COX inhibitors include,ibuprofen and naproxen. Inhibition of COX-1, which is found inplatelets, GI tract, kidneys and most other human tissues, is thought tobe associated with adverse effects such as gastrointestinal bleeding.The development of selective COX-2 NSAIDs, such as Celecoxib, Valdecoxiband Rofecoxib, have the benefits of non-selective NSAIDs with reducedadverse effect profiles in the gut and kidney. However, evidence nowsuggests that chronic use of certain selective COX-2 inhibitors canresult in an increased risk of stroke occurrence.

The use of opioid analgesics is recommended by the American Pain Societyto be initiated based on a pain-directed history and physical thatincludes repeated pain assessment. Due to the broad adverse effectprofiles associated with opiate use, therapy should include a diagnosis,integrated interdisciplinary treatment plan and appropriate ongoingpatient monitoring. It is further recommended that opioids be added tonon-opioids to manage acute pain and cancer related pain that does notrespond to non-opioids alone. Opioid analgesics act as agonists tospecific receptors of the mu and kappa types in the central andperipheral nervous system. Depending on the opioid and its formulationor mode of administration it can be of shorter or longer duration. Allopioid analgesics have a risk of causing respiratory depression, liverfailure, addiction and dependency, and as such are not ideal forlong-term or chronic pain management.

A number of other classes of drugs may enhance the effects of opioids orNSAIDSs, have independent analgesic activity in certain situations, orcounteract the side effects of analgesics. Regardless of which of theseactions the drug has, they are collectively termed “coanalgesics”.Tricyclic antidepressants, antiepileptic drugs, local anaesthetics,glucocorticoids, skeletal muscle relaxants, anti-spasmodil agents,antihistamines, benzodiazepines, caffeine, topical agents (e.g.capsaicin), dextroamphetamine and phenothizines are all used in theclinic as adjuvant therapies or individually in the treatment of pain.The antiepeileptic drugs in particular have enjoyed some success intreating pain conditions. For instance, Gabapentin, which has anunconfirmed therapeutic target, is indicated for neuropathic pain. Otherclinical trials are attempting to establish that central neuropathicpain may respond to ion channel blockers such as blockers of calcium,sodium and/or NMDA (N-methyl-D-aspartate) channels. Currently indevelopment are low affinity NMDA channel blocking agents for thetreatment of neuropathic pain. The literature provides substantialpre-clinical electrophysiological evidence in support of the use of NMDAantagonists in the treatment of neuropathic pain. Such agents also mayfind use in the control of pain after tolerance to opioid analgesiaoccurs, particularly in cancer patients.

Systemic analgesics such as NSAIDs and opioids are to be distinguishedfrom therapeutic agents which are useful only as localanalgesics/anaesthetics. Well known local analgesics such as lidocaineand xylocaine are non-selective ion channel blockers which can be fatalwhen administered systemically. A good description of non-selectivesodium channel blockers is found in Madge, D. et al., J. Med. Chem.(2001), 44(2):115-37.

Several sodium channel modulators are known for use as anticonvulsantsor antidepressants, such as carbamazepine, amitriptyline, lamotrigineand riluzole, all of which target brain tetradotoxin-sensitive (TTX-S)sodium channels. Such TTX-S agents suffer from dose-limiting sideeffects, including dizziness, ataxia and somnolence, primarily due toaction at TTX-S channels in the brain.

Sodium Channels Role in Pain

Sodium channels play a diverse set of roles in maintaining normal andpathological states, including the long recognized role that voltagegated sodium channels play in the generation of abnormal neuronalactivity and neuropathic or pathological pain (Chung, J. M. et al.).Damage to peripheral nerves following trauma or disease can result inchanges to sodium channel activity and the development of abnormalafferent activity including ectopic discharges from axotomised afferentsand spontaneous activity of sensitized intact nociceptors. These changescan produce long-lasting abnormal hypersensitivity to normally innocuousstimuli, or allodynia. Examples of neuropathic pain include, but are notlimited to, post-herpetic neuralgia, trigeminal neuralgia, diabeticneuropathy, chronic lower back pain, phantom limb pain, and painresulting from cancer and chemotherapy, chronic pelvic pain, complexregional pain syndrome and related neuralgias.

There has been some degree of success in treating neuropathic painsymptoms by using medications, such as gabapentin, and more recentlypregabalin, as short-term, first-line treatments. However,pharmacotherapy for neuropathic pain has generally had limited successwith little response to commonly used pain reducing drugs, such asNSAIDS and opiates. Consequently, there is still a considerable need toexplore novel treatment modalities.

There remains a limited number of potent effective sodium channelblockers with a minimum of adverse events in the clinic. There is alsoan unmet medical need to treat neuropathic pain and other sodium channelassociated pathological states effectively and without adverse sideeffects. The present invention provides compounds, methods of use andcompositions that include these compounds to meet these critical needs.

SUMMARY OF THE INVENTION

The present invention is directed to spiro-oxindole compounds that areuseful for the treatment and/or prevention of sodium channel-mediateddiseases or conditions, such as pain. The compounds of the presentinvention are also useful for the treatment of other sodiumchannel-mediated diseases or conditions, including, but not limited tocentral nervous conditions such as epilepsy, anxiety, depression andbipolar disease; cardiovascular conditions such as arrhythmias, atrialfibrillation and ventricular fibrillation; neuromuscular conditions suchas restless leg syndrome, essential tremour and muscle paralysis ortetanus; neuroprotection against stroke, glaucoma, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome.

Accordingly, in one aspect, the invention provides compounds of formula(I):

wherein:

-   j and k are each independently 0, 1, 2 or 3;-   Q is —C(R^(1a))H—, —C(O)—, —O—, —S(O)_(m)— (where m is 0, 1 or 2),    —CF₂—, —C(O)O—, —C(O)N(R⁵)— or —N(R⁵)C(O)—;-   R^(1a) is hydrogen or —OR⁵;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   or R¹ is aralkyl substituted by —C(O)N(R⁶)R⁷ where:    -   R⁶ is hydrogen, alkyl, aryl or aralkyl; and    -   R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵, —R⁹—N(R⁴)R⁵,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl or heteroarylalkyl;    -   or R⁶ and R⁷, together with the nitrogen to which they are        attached, form a heterocyclyl or heteroaryl;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R⁶ and R⁷ may be optionally substituted by one or more        substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵,        heterocyclyl and heteroaryl;-   or R¹ is aralkyl optionally substituted by one or more substituents    selected from the group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo,    haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and    heteroaryl;-   or R¹ is —R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹    where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵,        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹—OR⁵, or —R⁹—CN;        and    -   R¹² is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁵;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   or R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸NO₂;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁹ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, the invention provides methods for the treatment ofpain in a mammal, preferably a human, wherein the methods compriseadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of the invention as set forth above.

In another aspect, the present invention provides a method for treatingor lessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of Na_(v)1.1, Na_(v)1.2,Na_(v)1.3, Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, orNa_(v)1.9 is implicated in the disease state. In another aspect, theinvention provides methods of treating a range of sodiumchannel-mediated diseases or conditions, for example, pain associatedwith HIV, HIV treatment induced neuropathy, trigeminal neuralgia,post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis,irritable bowel syndrome, Crohns disease, pain associated with multiplesclerosis (MS), amyotrophic lateral sclerosis (ALS), diabeticneuropathy, peripheral neuropathy, arthritic, rheumatoid arthritis,osteoarthritis, atherosclerosis, paroxysmal dystonia, myastheniasyndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses, familialerythermalgia, primary erythermalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke, glaucoma or neural trauma, tachy-arrhythmias, atrialfibrillation and ventricular fibrillation.

In another aspect, the invention provides methods of treating a range ofsodium channel-mediated disease or condition through inhibition of ionflux through a voltage-dependent sodium channel in a mammal, preferablya human, wherein the methods comprise administering to the mammal inneed thereof a therapeutically effective amount of a compound of theinvention as set forth above.

In another aspect, the invention provides pharmaceutical compositionscomprising the compounds of the invention, as set forth above, andpharmaceutically acceptable excipients. In one embodiment, the presentinvention relates to a pharmaceutical composition comprising a compoundof the invention in a pharmaceutically acceptable carrier and in anamount effective to treat diseases or conditions related to pain whenadministered to an animal, preferably a mammal, most preferably a human.

In another aspect, the invention provides pharmaceutical therapy incombination with one or more other compounds of the invention or one ormore other accepted therapies or as any combination thereof to increasethe potency of an existing or future drug therapy or to decrease theadverse events associated with the accepted therapy. In one embodiment,the present invention relates to a pharmaceutical composition combiningcompounds of the present invention with established or future therapiesfor the indications listed in the invention.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

Certain chemical groups named herein are preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described. Forexample, the following terms have the meaning indicated:

“C₁-C₁₀alkyl” refers to an alkyl radical as defined below containing oneto ten carbon atoms. The C₁-C₁₀alkyl readical may be optionallysubstituted as defined below for an alkyl group.

“C₂-C₁₂alkynyl” refers to an alknyl radical as defined below containingtwo to twelve carbon atoms. The C₂-C₁₂alknyl radical may be optionallysubstituted as defined below for an alkenyl group.

“C₁-C₁₂alkoxy” refers to an alkoxy radical as defined below containingone to twelve carbon atoms. The alkyl part of the C₁-C₁₂alkoxy radicalmay be optionally substituted as defined below for an alkyl group.

“C₂-C₁₂alkoxyalkyl” refers to an alkoxyalkyl radical as defined belowcontaining two to twelve carbon atoms. Each alkyl part of theC₂-C₁₂alkoxyalkyl radical may be optionally substituted as defined belowfor an alkyl group.

“C₇-C₁₂aralkyl” refers to an aralkyl group as defined below containingseven to twelve carbon atoms. The aryl part of the C₇-C₁₂aralkyl radicalmay be optionally substituted as described below for an aryl group. Thealkyl part of the C₇-C₁₂aralkyl radical may be optionally substituted asdefined below for an alkyl group.

“C₇-C₁₂aralkenyl” refers to an aralkenyl group as defined belowcontaining seven to twelve carbon atoms. The aryl part of theC₇-C₁₂aralkenyl radical may be optionally substituted as described belowfor an aryl group. The alkenyl part of the C₇-C₁₂aralkenyl radical maybe optionally substituted as defined below for an alkenyl group.

“C₃-C₁₂cycloalkyl” refers to a cycloalkyl radical as defined belowhaving three to twelve carbon atoms. The C₃-C₁₂cycloalkyl radical may beoptionally substituted as defined below for a cycloalkyl group.

“C₄-C₁₂cycloalkylalkyl” refers to a cycloalkylalkyl radical as definedbelow having four to twelve carbon atoms. The C₄-C₁₂cycloalkylalkylradical may be optionally substituted as defined below for acycloalkylalkyl group.

In addition to the foregoing, as used in the specification and appendedclaims, unless specified to the contrary, the following terms have themeaning indicated:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Trifluoromethyl” refers to the —CF₃ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms, and which is attached tothe rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl(t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted by one of the following groups:alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴,—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶,—N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2), —S(O)_(t)OR¹⁶(where t is 1 to 2), —S(O)_(t)R¹⁶ (where t is 0 to 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to twelve carbon atoms,preferably one to eight carbon atoms and which is attached to the restof the molecule by a single bond, e.g., ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless statedotherwise specifically in the specification, an alkenyl group may beoptionally substituted by one of the following groups: alkyl, alkenyl,halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl,heteroaryl, oxo, trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂,—C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶,—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2), —S(O)_(t)OR¹⁶ (where t is 1 to2), —S(O)R¹⁶ (where t is 0 to 2), and —S(O)_(t)N(R¹⁴)₂ (where t is 1 to2) where each R¹⁴ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heteroarylalkyl; and each R¹⁶ is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, and where each of the above substituentsis unsubstituted unless otherwise indicated.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single bond and to the radical groupthrough a single bond. The points of attachment of the alkylene chain tothe rest of the molecule and to the radical group can be through onecarbon or any two carbons within the chain. Unless stated otherwisespecifically in the specification, an alkylene chain may be optionallysubstituted by one of the following groups: alkyl, alkenyl, halo,haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl,oxo, trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴,—C(O)OR¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (wheret is 1 to 2), —S(O)_(t)OR¹⁶ (where t is 1 to 2), —S(O)_(t)R¹⁶ (where tis 0 to 2), and —S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2) where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, e.g.,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a single bond andto the radical group through a double bond or a single bond. The pointsof attachment of the alkenylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain. Unless stated otherwise specifically in the specification, analkenylene chain may be optionally substituted by one of the followinggroups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR¹⁴,—OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2), —S(O)_(t)OR¹⁶(where t is 1 to 2), —S(O)_(t)R¹⁶ (where t is 0 to 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, e.g.,propynylene, n-butynylene, and the like. The alkynylene chain isattached to the rest of the molecule through a single bond and to theradical group through a double bond or a single bond. The points ofattachment of the alkynylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain. Unless stated otherwise specifically in the specification, analkynylene chain may be optionally substituted by one of the followinggroups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR¹⁴,—OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2),—S(O)_(t)OR¹⁶ (where t is 1 to 2), —S(O)_(t)R¹⁶ (where t is 0 to 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to twelve carbon atoms,preferably one to eight carbon atoms and which is attached to the restof the molecule by a single bond, e.g., ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. Unless stated otherwise specifically inthe specification, an alkynyl group may be optionally substituted by oneof the following groups: alkyl, alkenyl, halo, haloalkyl, haloalkenyl,cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —OR¹⁴, —OC(O)—R¹⁴,—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶,—N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2), —S(O)_(t)OR¹⁶(where t is 1 to 2), —S(O)_(t)R¹⁶ (where t is 0 to 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.The alkyl part of the alkoxy radical may be optionally substituted asdefined above for an alkyl radical.

“Alkoxyalkyl” refers to a radical of the formula —R_(a)—O—R_(a) whereeach R_(a) is independently an alkyl radical as defined above. Theoxygen atom may be bonded to any carbon in either alkyl radical. Eachalkyl part of the alkoxyalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Aryl” refers to aromatic monocyclic or multicyclic hydrocarbon ringsystem consisting only of hydrogen and carbon and containing from 6 to18 carbon atoms, where the ring system may be partially saturated. Arylgroups include, but are not limited to groups such as fluorenyl, phenyland naphthyl. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl, akenyl, halo,haloalkyl, haloalkenyl, cyano, nitro, aryl, heteroaryl, heteroarylalkyl,—R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶,—R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶ (where tis 1 to 2), —R¹⁵—S(O)_(t)R¹⁶ (where t is 1 to 2), —R¹⁵—S(O)_(t)OR¹⁶(where t is 1 to 2) where each R¹⁴ is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵ isindependently a direct bond or a straight or branched alkylene oralkenylene chain; and each R¹⁶ is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, and where each of the above substituentsis unsubstituted.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above and R_(b) is one or more aryl radicalsas defined above, e.g., benzyl, diphenylmethyl and the like. The arylradical(s) may be optionally substituted as described above.

“Aryloxy” refers to a radical of the formula —OR_(b) where R_(b) is anaryl group as defined above. The aryl part of the aryloxy radical may beoptionally substituted as defined above.

“Aralkenyl” refers to a radical of the formula —R_(c)R_(b) where R_(c)is an alkenyl radical as defined above and R_(b) is one or more arylradicals as defined above, which may be optionally substituted asdescribed above. The aryl part of the aralkenyl radical may beoptionally substituted as described above for an aryl group. The alkenylpart of the aralkenyl radical may be optionally substituted as definedabove for an alkenyl group.

“Aralkyloxy” refers to a radical of the formula —OR_(b) where R_(b) isan aralkyl group as defined above. The aralkyl part of the aralkyloxyradical may be optionally substituted as defined above.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptly, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.Unless otherwise stated specifically in the specification, the term“cycloalkyl” is meant to include cycloalkyl radicals which areoptionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴,—R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2),—R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2), —R¹⁵—S(O)_(t)R¹⁶ (where t is 0 to2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; each R¹⁵ is independently a direct bond or a straightor branched alkylene or alkenylene chain; and each R¹⁶ is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of theabove substituents is unsubstituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a cycloalkylradical as defined above. The alkyl radical and the cycloalkyl radicalmay be optionally substituted as defined above.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of two to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.Unless stated otherwise specifically in the specification, the term“heterocyclyl” is meant to include heterocyclyl radicals as definedabove which are optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴,—R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ where t is 1 or 2),—R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2), —R¹⁵—S(O)_(t)R¹⁶ (where t is 0 to2), and —R¹⁵—S(O)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ isindependently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R¹⁵ is independently a direct bondor a straight or branched alkylene or alkenylene chain; and each R¹⁶ isalkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(e) whereR_(a) is an alkyl radical as defined above and R_(e) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The alkyl part of theheterocyclylalkyl radical may be optionally substituted as defined abovefor an alkyl group. The heterocyclyl part of the heterocyclylalkylradical may be optionally substituted as defined above for aheterocyclyl group.

“Heteroaryl” refers to a 5- to 18-membered aromatic ring radical whichconsists of one to seventeen carbon atoms and from one to tenheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. For purposes of this invention, the heteroaryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heteroaryl radical may be optionally oxidized; thenitrogen atom may be optionally quaternized. Examples include, but arenot limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl,benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, the term “heteroaryl” is meant toinclude heteroaryl radicals as defined above which are optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl,cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, 'R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴,—R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2),—R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2), —R¹⁵—S(O)_(t)R¹⁶ (where t is 0 to2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ isindependently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R¹⁵ is independently a direct bondor a straight or branched alkylene or alkenylene chain; and each R¹⁶ isalkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(a)R_(f) whereR_(a) is an alkyl radical as defined above and R_(f) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkylradical may be optionally substituted as defined above for a heteroarylgroup. The alkyl part of the heteroarylalkyl radical may be optionallysubstituted as defined above for an alkyl group.

“Heteroarylalkenyl” refers to a radical of the formula —R_(b)R_(f) whereR_(b) is an alkenyl radical as defined above and R_(f) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkenylradical may be optionally substituted as defined above for a heteroarylgroup. The alkenyl part of the heteroarylalkenyl radical may beoptionally substituted as defined above for an alkenyl group.

“Trihaloalkyl” refers to an alkyl radical, as defined above, that issubstituted by three halo radicals, as defined above, e.g.,trifluoromethyl. The alkyl part of the trihaloalkyl radical may beoptionally substituted as defined above for an alkyl group.

“Trihaloalkoxy” refers to a radical of the formula —OR_(g) where R_(g)is a trihaloalkyl group as defined above. The trihaloalkyl part of thetrihaloalkoxy group may be optionally substituted as defined above for atrihaloalkyl group.

“Analgesia” refers to an absence of pain in response to a stimulus thatwould normally be painful.

“Allodynia” refers to a condition in which a normally innocuoussensation, such as pressure or light touch, is perceived as beingextremely painful.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam)).A discussion of prodrugs is provided in Higuchi,T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. SymposiumSeries, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound of the invention in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amide derivatives of amine functional groupsin the compounds of the invention and the like.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of formula (I) beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction on the sodium channels, or binding affinity to pharmacologicallyimportant site of action on the sodium channels. Certainisotopically-labelled compounds of formula (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples and Preparations as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reducation, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products are typically are identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itscoversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets, (e.g. cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildelife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a sodiumchannel-mediated disease or condition in the mammal, preferably a human.The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the condition and its severity, the manner of administration, and theage of the mammal to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition.As used herein, the terms “disease” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (-), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallisation. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

Also within the scope of the invention are intermediate compounds offormula (I) and all polymorphs of the aforementioned species and crystalhabits thereof.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ACD/NameVersion 9.07 software program, wherein the compounds of the inventionare named herein as derivatives of the central core structure, i.e., the2-oxindole structure. For complex chemical names employed herein, asubstituent group is named before the group to which it attaches. Forexample, cyclopropylethyl comprises an ethyl backbone with cyclopropylsubstituent. In chemical structure diagrams, all bonds are identified,except for some carbon atoms, which are assumed to be bonded tosufficient hydrogen atoms to complete the valency.

Thus, for example, a compound of formula (I) wherein j is 0, k is 1, Qis —O—, R¹ is pentyl, R^(2a) is 3,5-dichlorophenyl, R^(2b), R^(2c) andR^(2d) are each hydrogen, R^(3a) and R^(3d) are each hydrogen, andR^(3b) and R^(3c), together with the carbon ring atoms to which they areattached, form a fused dioxolyl ring; i.e., a compound of the followingformula:

is named herein as4′-(3,5-dichlorophenyl)-1-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one.

EMBODIMENTS OF THE INVENTION

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments are preferred.

One embodiment of the invention are the compounds of formula (I) as setforth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is 0,    1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2b) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2d)    are as defined above;    -   or R^(2c) and R^(2d), together with the carbon ring atoms to        which they are directly attached, may form a fused ring selected        from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a)        and R^(2b) are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from hydrogen, halo or alkyl;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3c)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, —R⁸—OR⁵, —R⁸—C(O)R⁵, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵,    —S(O)₂—R⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from hydrogen, halo or alkyl;-   R^(3a) and R^(3d) are both hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the Invention wherein:

-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, —R⁸—OR⁵, —R⁸—C(O)R⁵, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵,    —S(O)₂—R⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from hyrdogen, halo or alkyl;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the Invention wherein:

-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, —R⁸—OR⁵, —R⁸—C(O)R⁵, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵,    —S(O)₂—R⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from hydrogen, halo or alkyl;-   R^(3a) and R^(3d) are both hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused optionally substituted    heterocyclyl ring or a fused optionally substituted cycloalkyl ring;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the Invention wherein:

-   R¹ is aryl, heteroaryl or heterocyclyl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen; and-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is hydrogen, alkyl, —R⁸—C(O)OR⁵ or —R⁸—C(O)N(R⁴)R⁵;-   R^(2a) is selected from the group consisting of hydrogen, alkyl,    alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(e)a is optionally substituted        by one or more substituents selected from the group consisting        of alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,        haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,        heteroarylalkyl, —R⁸—CN, —R⁸NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵,        —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵, —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴,        —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and —N(R⁵)S(O)_(n)R⁴, wherein        each m is independently 0, 1, or 2 and each n is independently 1        or 2;-   R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from hydrogen or halo;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl and R^(3a) and R^(3d)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or j is 1 and k is 0;-   Q is —O—;-   R¹ is hydrogen or alkyl;-   R^(2a) is selected from the group consisting of alkyl, haloalkenyl,    aryl, aralkyl, aralkenyl, heterocyclyl, heteroaryl, —R⁸—C(O)N(R⁴)R⁵,    and —R⁸—N(R⁴)R⁵;    -   wherein each of the aryl, aralkyl, aralkenyl, heterocyclyl and        heteroaryl groups for R^(2a) is optionally substituted by one or        more substituents selected from the group consisting of alkyl,        alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,        haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,        aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,        heteroarylalkyl, —R⁸—CN, —R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵,        —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵, —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴,        —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and —N(R⁵)S(O)_(n)R⁴, wherein        each m is independently 0, 1, or 2 and each n is independently 1        or 2;-   R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from hydrogen or halo;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, form a fused dioxolyl ring or a fused    optionally substituted tetrahydrofuranyl ring, and R^(3a) and R^(3d)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl; and-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is aralkyl substituted by —C(O)N(R⁶)R⁷ where:    -   R⁶ is hydrogen, alkyl, aryl or aralkyl; and    -   R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵, —R⁹—N(R⁴)R⁵,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl or heteroarylalkyl;    -   or R⁶ and R⁷, together with the nitrogen to which they are        attached, form a heterocyclyl or heteroaryl;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R⁶ and R⁷ may be optionally substituted by one or more        substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵,        heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴,    —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3b) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is aralkyl substituted by —C(O)N(R⁶)R⁷ where:    -   R⁶ is hydrogen, alkyl, aryl or aralkyl; and    -   R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵, —R⁹—N(R⁴)R⁵,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl or heteroarylalkyl;    -   or R⁶ and R⁷, together with the nitrogen to which they are        attached, form a heterocyclyl or heteroaryl;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R⁶ and R⁷ may be optionally substituted by one or more        substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵,        heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused ring selected from cycloalkyl,    heterocyclyl, aryl or heteroaryl;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and each R⁹ is a straight or branched alkylene    chain, a straight or branched alkenylene chain or a straight or    branched alkynylene chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is aralkyl substituted by —C(O)N(R⁶)R⁷ where:    -   R⁶ is hydrogen, alkyl, aryl or aralkyl; and    -   R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵ or        —R⁹—N(R⁴)R⁵;    -   or R⁶ and R⁷, together with the nitrogen to which they are        attached, form a heterocyclyl or heteroaryl;    -   wherein each aryl, aralkyl, heterocyclyl and heteroaryl groups        for R⁶ and R⁷ is optionally substituted by one or more        substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵,        heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is aralkyl substituted by —C(O)N(R⁶)R⁷ where:    -   R⁶ is hydrogen, alkyl, aryl or aralkyl; and    -   R⁷ is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl or heteroarylalkyl;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R⁶ and R⁷ may be optionally substituted by one or more        substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵,        heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is aralkyl optionally substituted by one or more substituents    selected from the group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo,    haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and    heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵, —R⁸—C(O)N(R⁴)R⁵,        —N(R⁵)C(O)R⁴, and —N(R⁵)S(O)_(n)R⁴, wherein each m is        independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is aralkyl optionally substituted by one or more substituents    selected from the group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo,    haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and    heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from hydrogen, alkyl or halo;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl; and-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is aralkyl optionally substituted by one or more substituents    selected from the group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo,    haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and    heteroaryl;-   R^(2a), R^(2b), R^(2d) and R^(2d) are each independently selected    from hydrogen, alkyl or halo;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, halo, and —R⁸—OR⁵-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, dioxolyl, tetrahydrofuranyl, and heteroaryl, and R^(3a)    and R^(3d) are each hydrogen;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl; and-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is —R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹¹ where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵,        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹—OR⁵, or —R⁹—CN;        and    -   R¹² is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁵;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—C(O)R⁴, —C(S)R⁴,    —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵,    —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴,    —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵, —N(R⁵)S(O)_(n)R⁴,    —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵, —N(R⁵)C(═NR⁵)N(R⁴)R⁵,    and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is independently 0, 1, or    2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁹ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is —R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹    where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵,        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹—OR⁵, or —R⁹—CN;        and    -   R¹² is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁵;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused ring selected from cycloalkyl,    heterocyclyl, aryl or heteroaryl;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁹ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is —R⁹—N(R¹⁰)R¹¹ where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵,        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹—OR⁵, or —R⁹—CN;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is —R⁹—N(R¹²)C(O)R¹¹ where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵,        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹OR⁵, or —R⁹—CN; and    -   R¹² is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁵;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹ where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵,        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹—OR⁵, or —R⁹—CN;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸—NO₂;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸—NO₂;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from hydrogen, halo, alkyl or —R⁸—OR⁵;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from hydrogen, halo, alkyl or —R⁸—OR⁵;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are each hydrogen;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl; and-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1;-   Q is —O—;-   R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸—NO₂;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from hydrogen, halo, alkyl or —R⁸—OR⁵;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from hydrogen, halo, alkyl or —R⁸—OR⁵;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from dioxolyl    or tetrahydrofuranyl, and R^(3a) and R^(3d) are each hydrogen;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl; and-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸—NO₂;-   R^(2a), R^(2b), R^(2c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   R^(3a) and R^(3d) are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo,    haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl,    aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵,    —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃, —R⁸—C(O)R⁴, —C(S)R⁴)₂C(O)R⁵,    —R⁸—C(O)OR⁴, —C(S)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴,    —N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵,    —N(R⁵)C(S)N(R⁴)R⁵, —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵,    —R⁸—S(O)_(n)N(R⁴)R⁵, —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and    —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m is independently 0, 1, or    2 and each n is independently 1 or 2;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    dioxolyl or tetrahydrofuranyl, and R^(3a) and R^(3d) are as defined    above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   at least one of j and k is 1 and the other is 0 or 1;-   Q is —O—;-   R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸—NO₂;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    aikoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —O—;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   R^(2a), R^(2b), and R^(3d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused ring selected from cycloalkyl,    heterocyclyl, aryl or heteroaryl;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —C(R^(1a))H—, —C(O)—, —CF₂—, —C(O)O— or —N(R⁵)C(O)—;-   R^(1a) is hydrogen or —OR⁵;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   or R¹ is aralkyl substituted by —C(O)N(R⁶)R⁷ where:    -   R⁶ is hydrogen, alkyl, aryl or aralkyl; and    -   R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵, —R⁹—N(R⁴)R⁵,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl or heteroarylalkyl;    -   or R⁶ and R⁷, together with the nitrogen to which they are        attached, form a heterocyclyl or heteroaryl;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R⁶ and R⁷ may be optionally substituted by one or more        substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵,        heterocyclyl and heteroaryl;-   or R¹ is aralkyl optionally substituted by one or more substituents    selected from the group consisting of —R⁸—OR⁵, —C(O)OR^(S), halo,    haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and    heteroaryl;-   or R¹ is —R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹    where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR^(S),        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹—OR⁵, or —R⁹—CN;        and    -   R¹² is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁵;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   or R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸—NO₂;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N*R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(a3), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —C(R^(1a))H—;-   R^(1a) is hydrogen or —OR⁵;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN—R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —C(R^(1a))H—;-   R^(1a) is hydrogen or —OR⁵;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;    -   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused ring selected from cycloalkyl,    heterocyclyl, aryl or heteroaryl;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —C(R^(1a))H—;-   R^(1a) is hydrogen or —OR⁵;-   R¹ is pentyl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring; and-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —C(O)—, —CF₂—, —C(O)O— or —N(R⁵)C(O)—;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;-   or R¹ is aralkyl substituted by —C(O)N(R⁶)R⁷ where:    -   R⁶ is hydrogen, alkyl, aryl or aralkyl; and    -   R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵, —R⁹—N(R⁴)R⁵,        aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl or heteroarylalkyl;    -   or R⁶ and R⁷, together with the nitrogen to which they are        attached, form a heterocyclyl or heteroaryl;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R⁶ and R⁷ may be optionally substituted by one or more        substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵,        heterocyclyl and heteroaryl;-   or R¹ is aralkyl optionally substituted by one or more substituents    selected from the group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo,    haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and    heteroaryl;-   or R¹ is —R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹    where:    -   each R¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl;    -   each R¹¹ is hydrogen, alkyl, haloalkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, heteroarylalkyl, —R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵,        —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵, —R⁹—OR⁵, or —R⁹—CN;        and    -   R¹² is hydrogen, alkyl, aryl, aralkyl or —C(O)R⁵;    -   and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl        group for R¹⁰ and R¹¹ may be optionally substituted by one or        more substituents selected from the group consisting of alkyl,        cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN,        —R⁸—OR⁵, —R⁸—C(O)R⁵, heterocyclyl and heteroaryl;-   or R¹ is heterocyclylalkyl or heteroarylalkyl where the    heterocyclylalkyl or the heteroarylalkyl group is optionally    substituted by one or more substituents selected from the group    consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,    heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,    —R⁸C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or    2), —R⁸—CN, or —R⁸—NO₂;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is    independently 0, 1, or 2 and each n is independently 1 or 2;    -   and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,        aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl        and heteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d)        may be optionally substituted by one or more substituents        selected from the group consisting of alkyl, alkenyl, alkynyl,        alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,        —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,        —R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and        —N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and        each n is independently 1 or 2;-   or R^(2a) and R^(2b), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d)    are as defined above;-   or R^(2b) and R^(2c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2d)    are as defined above;-   or R^(2c) and R^(2d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a) and R^(2b)    are as defined above;-   R^(3a), R^(3b), R^(3c) and R^(3d) are each independently selected    from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,    alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,    cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,    —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,    —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,    —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,    —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,    —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,    —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m    is independently 0, 1, or 2 and each n is independently 1 or 2;-   or R^(3a) and R^(3b), together with the carbon ring atoms to which    they are directly attached, form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3b) and R^(3c), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d)    are as defined above;-   or R^(3c) and R^(3d), together with the carbon ring atoms to which    they are directly attached, may form a fused ring selected from    cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3b)    are as defined above;-   each R⁴ and R⁵ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,    heterocyclylalkyl, heteroaryl, and heteroarylalkyl;-   or when R⁴ and R⁵ are each attached to the same nitrogen atom, then    R⁴ and R⁵, together with the nitrogen atom to which they are    attached, may form a heterocyclyl or heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —C(O)—, —CF₂—, —C(O)O— or —N(R⁵)C(O)—;-   R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,    cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,    —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is    0, 1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵;    -   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused ring selected from cycloalkyl,    heterocyclyl, aryl or heteroaryl;-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl;-   each R⁸ is a direct bond or a straight or branched alkylene chain, a    straight or branched alkenylene chain or a straight or branched    alkynylene chain; and-   each R⁹ is a straight or branched alkylene chain, a straight or    branched alkenylene chain or a straight or branched alkynylene    chain.

Another embodiment of the invention are the compounds of formula (I) asset forth above in the Summary of the invention wherein:

-   j is 0 and k is 1 or 2;-   Q is —C(O)—, —CF₂—, —C(O)O— or —N(R⁵)C(O)—;-   R¹ is pentyl;-   R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;-   R^(3a) and R^(3d) are each hydrogen;-   R^(3b) and R^(3c), together with the carbon ring atoms to which they    are directly attached, form a fused dioxolyl ring; and-   each R⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and    heteroaryl.

Specific embodiments of the compounds of formula (I) are described inmore detail below in the Preparation of the Compounds of the Invention.

UTILITY AND TESTING OF THE COMPOUNDS OF THE INVENTION

The present invention relates to compounds, pharmaceutical compositionsand methods of using the compounds and pharmaceutical compositions forthe treatment of sodium channel-mediated diseases, preferably diseasesrelated to pain, central nervous conditions such as epilepsy, anxiety,depression and bipolar disease; cardiovascular conditions such asarrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome, by administering to a patient in need ofsuch treatment an effective amount of a sodium channel blockermodulating, especially inhibiting, agent.

In general, the present invention provides a method for treating apatient for, or protecting a patient from developing, a sodiumchannel-mediated disease, especially pain, comprising administering toan animal, such as a mammal, especially a human patient in need thereof,a therapeutically effective amount of a compound of the invention or apharmaceutical composition comprising a compound of the inventionwherein the compound modulates the activity of one or morevoltage-dependent sodium channels.

The general value of the compounds of the invention in mediating,especially inhibiting, the sodium channel ion flux can be determinedusing the assays described below in the Biological Assays section.Alternatively, the general value of the compounds in treating conditionsand diseases may be established in industry standard animal models fordemonstrating the efficacy of compounds in treating pain. Animal modelsof human neuropathic pain conditions have been developed that result inreproducible sensory deficits (allodynia, hyperalgesia, and spontaneouspain) over a sustained period of time that can be evaluated by sensorytesting. By establishing the degree of mechanical, chemical, andtemperature induced allodynia and hyperalgesia present, severalphysiopathological conditions observed in humans can be modeled allowingthe evaluation of pharmacotherapies.

In rat models of peripheral nerve injury, ectopic activity in theinjured nerve corresponds to the behavioural signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviourand motor function (Mao, J. and Chen, L. L, Pain (2000), 87:7-17).Allimetric scaling of the doses effective in these rat models,translates into doses similar to those shown to be efficacious in humans(Tanelian, D. L. and Brose, W. G., Anesthesiology (1991),74(5):949-951). Furthermore, Lidoderm®, lidocaine applied in the form ofa dermal patch, is currently an FDA approved treatment for post-herpeticneuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain (2000),16(3):205-8).

Sodium channel blockers have clinical uses in addition to pain. Epilepsyand cardiac arrhythmias are often targets of sodium channel blockers.Recent evidence from animal models suggest that sodium channel blockersmay also be useful for neuroprotection under ischaemic conditions causedby stroke or neural trauma and in patients with multiple sclerosis (MS)(Clare, J. J. et al., op. cit. and Anger, T. et al., op. cit.).

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel in a mammal, especially in ahuman. Any such modulation, whether it be partial or complete inhibitionor prevention of ion flux, is sometimes referred to herein as “blocking”and corresponding compounds as “blockers”. In general, the compounds ofthe invention modulates the activity of a sodium channel downwards,inhibits the voltage-dependent activity of the sodium channel, and/orreduces or prevents sodium ion flux across a cell membrane by preventingsodium channel activity such as ion flux.

The compounds of the instant invention are sodium channel blockers andare therefore useful for treating diseases and conditions in humans andother organisms, including all those human diseases and conditions whichare the result of aberrant voltage-dependent sodium channel biologicalactivity or which may be ameliorated by modulation of voltage-dependentsodium channel biological activity.

As defined herein, a sodium channel-mediated disease or condition refersto a disease or condition which is ameliorated upon modulation of thesodium channel and includes, but is not limited to, pain, centralnervous conditions such as epilepsy, anxiety, depression and bipolardisease; cardiovascular conditions such as arrhythmias, atrialfibrillation and ventricular fibrillation; neuromuscular conditions suchas restless leg syndrome and muscle paralysis or tetanus;neuroprotection against stroke, neural trauma and multiple sclerosis;and channelopathies such as erythromyalgia and familial rectal painsyndrome.

A sodium channel-mediated disease or condition also includes painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, glossopharyngeal neuralgia, neuropathy secondary tometastatic infiltration, adiposis dolorosa, thalamic lesions,hypertension, autoimmune disease, asthma, drug addiction (e.g. opiate,benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation),Alzheimer, dementia, age-related memory impairment, Korsakoff syndrome,restenosis, urinary dysfunction, incontinence, parkinson's disease,cerebrovascular ischemia, neurosis, gastrointestinal disease, sicklecell anemia, transplant rejection, heart failure, myocardial infarction,reperfusion injury, intermittant claudication, angina, convulsion,respiratory disorders, cerebral or myocardial ischemias, long-QTsyndrome, Catecholeminergic polymorphic ventricular tachycardia,ophthalmic diseases, spasticity, spastic paraplegia, myopathies,myasthenia gravis, paramyotonia congentia, hyperkalemic periodicparalysis, hypokalemic periodic paralysis, alopecia, anxiety disorders,psychotic disorders, mania, paranoia, seasonal affective disorder, panicdisorder, obsessive compulsive disorder (OCD), phobias, autism,Aspergers Syndrome, Retts syndrome, disintegrative disorder, attentiondeficit disorder, aggressivity, impulse control disorders, thrombosis,pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich'sataxia, Spinocerebellear ataxia, myelopathy, radiculopathy, systemiclupus erythamatosis, granulomatous disease, olivo-ponto-cerebellaratrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressivepallidal atrophy, progressive supranuclear palsy and spasticity,traumatic brain injury, cerebral oedema, hydrocephalus injury, spinalcord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity,optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy,retinitis pigmentosa, acute and chronic glaucoma, macular degeneration,retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema,proctitis, post-herpetic neuralgia, eudynia, heat sensitivity,sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-NyhanSyndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiplesclerosis and the pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabeticneuropathy, peripheral neuropathy, charcot marie tooth syndrome,arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap,hypothyroidism, bipolar depression, anxiety, schizophrenia, sodiumchannel toxin related illnesses, familial erythermalgia, primaryerythermalgia, rectal pain, cancer, epilepsy, partial and general tonicseizures, febrile seizures, absence seizures (petit mal), myoclonicseizures, atonic seizures, clonic seizures, Lennox Gastaut, West Syndome(infantile spasms), multiresistant seizures, seizure prophylaxis(anti-epileptogenic), familial Mediterranean fever syndrome, gout,restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection underischaemic conditions caused by stroke or neural trauma,tachy-arrhythmias, atrial fibrillation and ventricular fibrillation andas a general or local anaesthetic.

As used herein, the term “pain” refers to all categories of pain and isrecognized to include, but is not limited to, neuropathic pain,inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain,orofacial pain, burn pain, burning mouth syndrome, somatic pain,visceral pain, myofacial pain, dental pain, cancer pain, chemotherapypain, trauma pain, surgical pain, post-surgical pain, childbirth pain,labor pain, reflex sympathetic dystrophy, brachial plexus avulsion,neurogenic bladder, acute pain (e.g. musculoskeletal and post-operativepain), chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, familialhemiplegic migraine, conditions associated with cephalic pain, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,pain following stroke, thalamic lesions, radiculopathy,HIV pain,post-herpetic pain, non-cardiac chest pain, irritable bowel syndrome andpain associated with bowel disorders and dyspepsia, and combinationsthereof.

The compounds identified in the instant specification inhibit the ionflux through a voltage-dependent sodium channel. Preferably, thecompounds are state or frequency dependent modifers of the sodiumchannels, having a low affinity for the rested/closed state and a highaffinity for the inactivated state. These compounds are likely tointeract with overlapping sites located in the inner cavity of thesodium conducting pore of the channel similar to that described forother state-dependent sodium channel blockers (Cestèle, S., et al., op.cit.). These compounds may also be likely to interact with sites outsideof the inner cavity and have allosteric effects on sodium ion conductionthrough the channel pore.

Any of these consequences may ultimately be responsible for the overalltherapeutic benefit provided by these compounds.

The present invention readily affords many different means foridentification of sodium channel modulating agents that are useful astherapeutic agents. Identification of modulators of sodium channel canbe assessed using a variety of in vitro and in vivo assays, e.g.measuring current, measuring membrane potential, measuring ion flux,(e.g. sodium or guanidinium), measuring sodium concentration, measuringsecond messengers and transcription levels, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

One such protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

A competitive binding assay with known sodium channel toxins such astetrodotoxin, alpha-scorpion toxins, aconitine, BTX and the like, may besuitable for identifying potential therapeutic agents with highselectivity for a particular sodium channel. The use of BTX in such abinding assay is well known and is described in McNeal, E. T., et al.,J. Med. Chem. (1985), 28(3):381-8; and Creveling, C. R., et al., Methodsin Neuroscience, Vol.8: Neurotoxins (Conn PM Ed) (1992), pp. 25-37,Academic Press, New York.

These assays can be carried out in cells, or cell or tissue extractsexpressing the channel of interest in a natural endogenous setting or ina recombinant setting. The assays that can be used include plate assayswhich measure Na+influx through surrogate markers such as ¹⁴C-guanidineinflux or determine cell depolarization using fluorescent dyes such asthe FRET based and other fluorescent assays or a radiolabelled bindingassay employing radiolabelled aconitine, BTX, TTX or STX. More directmeasurements can be made with manual or automated electrophysiologysystems. The guanidine influx assay is explained in more detail below inthe Biological Assays section.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available, however these are of only limitedfunctional value and information content. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive²²[Na] and ¹⁴[C] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red, SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPRTM II FRET system (AuroraBiosciences Corporation, San Diego, Calif., a division of VertexPharmaceuticals, Inc.) which may be used in conjunction with FRET dyes,also available from Aurora Biosciences. This assay measures sub-secondresponses to voltage changes. There is no requirement for a modifier ofchannel function. The assay measures depolarization andhyperpolarizations, and provides ratiometric outputs for quantification.A somewhat less expensive MTS version of this assay employs theFLEXstation™ (Molecular Devices Corporation) in conjunction with FRETdyes from Aurora Biosciences. Other methods of testing the compoundsdisclosed herein are also readily known and available to those skilledin the art.

These results provide the basis for analysis of the structure-activityrelationship (SAR) between test compounds and the sodium channel.Certain substituents on the core structure of the test compound tend toprovide more potent inhibitory compounds. SAR analysis is one of thetools those skilled in the art may now employ to identify preferredembodiments of the compounds of the invention for use as therapeuticagents.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they alleviate pain, especially chronicpain or other conditions such as arrhythmias and epilepsy with minimaladverse events. The assays described below in the Biological AssaysSection are useful in assessing the biological activity of the instantcompounds.

Typically, a successful therapeutic agent of the present invention willmeet some or all of the following criteria. Oral availability should beat or above 20%. Animal model efficacy is less than about 0.1 pg toabout 100 mg/Kg body weight and the target human dose is between 0.1 pgto about 100 mg/Kg body weight, although doses outside of this range maybe acceptable (“mg/Kg” means milligrams of compound per kilogram of bodymass of the subject to whom it is being administered). The therapeuticindex (or ratio of toxic dose to therapeutic dose) should be greaterthan 100. The potency (as expressed by IC₅₀ value) should be less than10 μM, preferably below 1 μM and most preferably below 50 nM. The IC₅₀(“Inhibitory Concentration—50%”) is a measure of the amount of compoundrequired to achieve 50% inhibition of ion flux through a sodium channel,over a specific time period, in an assay of the invention. Compounds ofthe present invention in the guanidine influx assay have demonstratedIC-50s ranging from less than a nanomolar to less than 10 micromolar.

In an alternative use of the invention, the compounds of the inventioncan be used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting Na_(v)1.1,Na_(v)1.2, Na_(v)1.3, Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7,Na_(v)1.8, or Na_(v)1.9 activity in a biological sample or a patient,which method comprises administering to the patient, or contacting saidbiological sample with a compound of formula I or a compositioncomprising said compound. The term “biological sample”, as used herein,includes, without limitation, cell cultures or extracts thereof;biopsied material obtained from a mammal or extracts thereof; and blood,saliva, urine, feces, semen, tears, or other body fluids or extractsthereof.

Inhibition of Na_(v)1.1, Na_(v)1.2, Na_(v)1.3, Na_(v)1.4, Na_(v)1.5,Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, or Na_(v)1.9 activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, the study of sodium ion channels in biological and pathologicalphenomena; and the comparative evaluation of new sodium ion channelinhibitors.

PHARMACEUTICAL COMPOSITIONS OF THE INVENTION AND ADMINISTRATION

The present invention also relates to pharmaceutical compositioncontaining the compounds of the invention disclosed herein. In oneembodiment, the present invention relates to a composition comprisingcompounds of the invention in a pharmaceutically acceptable carrier andin an amount effective to modulate, preferably inhibit, ion flux througha voltage-dependent sodium channel to treat sodium channel mediateddiseases, such as pain, when administered to an animal, preferably amammal, most preferably a human patient.

The pharmaceutical compositions useful herein also contain apharmaceutically acceptable carrier, including any suitable diluent orexcipient, which includes any pharmaceutical agent that does not itselfinduce the production of antibodies harmful to the individual receivingthe composition, and which may be administered without undue toxicity.Pharmaceutically acceptable carriers include, but are not limited to,liquids, such as water, saline, glycerol and ethanol, and the like. Athorough discussion of pharmaceutically acceptable carriers, diluents,and other excipients is presented in REMINGTON′S PHARMACEUTICAL SCIENCES(Mack Pub. Co., N.J. current edition).

Those skilled in the art know how to determine suitable doses of thecompounds for use in treating the diseases and conditions contemplatedherein. Therapeutic doses are generally identified through a doseranging study in humans based on preliminary evidence derived fromanimal studies. Doses must be sufficient to result in a desiredtherapeutic benefit without causing unwanted side effects for thepatient.

A typical regimen for treatment of sodium channel-mediated diseasecomprises administration of an effective amount over a period of one orseveral days, up to and including between one week and about six months,or it may be chronic. It is understood that the dosage of adiagnostic/pharmaceutical compound or composition of the inventionadministered in vivo or in vitro will be dependent upon the age, sex,health, and weight of the recipient, severity of the symptons, kind ofconcurrent treatment, if any, frequency of treatment, the response ofthe individual, and the nature of the diagnostic/pharmaceutical effectdesired. The ranges of effective doses provided herein are not intendedto be limiting and represent preferred dose ranges. However, the mostpreferred dosage will be tailored to the individual subject, as isunderstood and determinable by one skilled in the relevant arts. (see,e.g., Berkowet al., eds., The Merck Manual, 16^(th) edition, Merck andCo., Rahway, N.J., 1992; Goodmanetna., eds.,Goodman and Cilman's ThePharmacological Basis of Therapeutics, 10^(th) edition, Pergamon Press,Inc., Elmsford, N.Y., (2001); Avery's Drug

Treatment: Principles and Practice of Clinical Pharmacology andTherapeutics, 3rd edition, ADIS Press, LTD., Williams and Wilkins,Baltimore, Md. (1987), Ebadi, Pharmacology, Little, Brown and Co.,Boston, (1985); Osolci al., eds., Remington's Pharmaceutical Sciences,18^(th) edition, Mack Publishing Co., Easton, Pa. (1990); Katzung, Basicand Clinical Pharmacology, Appleton and Lange, Norwalk, Conn. (1992)).

The total dose required for each treatment can be administered bymultiple doses or in a single dose over the course of the day, ifdesired. Generally, treatment is initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. The diagnostic pharmaceutical compound orcomposition can be administered alone or in conjunction with otherdiagnostics and/or pharmaceuticals directed to the pathology, ordirected to other symptoms of the pathology. Effective amounts of adiagnostic pharmaceutical compound or composition of the invention arefrom about 0.1 μg to about 100 mg/Kg body weight, administered atintervals of 4-72 hours, for a period of 2 hours to 1 year, and/or anyrange or value therein, such as 0.0001-0.001, 0.001-0.01, 0.01-0.1,0.1-1.0,1.0-10, 5-10, 10-20, 20-50 and 50-100 mg/Kg, at intervals of1-4, 4-10, 10-16, 16-24, 24-36, 24-36, 36-48, 48-72 hours, for a periodof 1-14, 14-28, or 30-44 days, or 1-24 weeks, any range or valuetherein. The recipients of administration of compounds and/orcompositions of the invention can be any vertebrate animal, such asmammals. Among mammals, the preferred recipients are mammals of theOrders Primate (including humans, apes and monkeys), Arteriodactyla(including horses, goats, cows, sheep, pigs), Rodenta (including mice,rats, rabbits, and hamsters), and Carnivora (including cats, and dogs).Among birds, the preferred recipients are turkeys, chickens and othermembers of the same order. The most preferred recipients are humans.

For topical applications, it is preferred to administer an effectiveamount of a pharmaceutical composition according to the invention totarget area, e.g., skin surfaces, mucous membranes, and the like, whichare adjacent to peripheral neurons which are to be treated. This amountwill generally range from about 0.0001 mg to about 1 g of a compound ofthe invention per application, depending upon the area to be treated,whether the use is diagnostic, prophylactic or therapeutic, the severityof the symptoms, and the nature of the topical vehicle employed. Apreferred topical preparation is an ointment, wherein about 0.001 toabout 50 mg of active ingredient is used per cc of ointment base. Thepharmaceutical composition can be be formulated as transdermalcompositions or transdermal delivery devices (“patches”). Suchcompositions include, for example, a backing, active compound reservoir,a control membrane, liner and contact adhesive. Such transdermal patchesmay be used to provide continuous pulsatile, or on demand delivery ofthe compounds of the present invention as desired.

The composition may be intended for rectal administration, in the form,e.g., of a suppository which will melt in the rectum and release thedrug. A typical suppository formulation will generally consist of activeingredient with a binding and/or lubricating agent such as a gelatine orcocoa butter or other low melting vegetable or synthetic wax or fat.

A typical formulation for intramuscular or intrathecal administrationwill consist of a suspension or solution of active in an oil or solutionof active ingredient in an oil, for example arachis oil or seasame oil.A typical formulation for intravenous or intrathecal administration willconsist of sterile isotonic aqueous solution containing, for exampleactive ingredient and dextrose or sodium chloride or a mixture ofdextrose and sodium chloride.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems include osmotic pump systemsand dissolutional systems containing polymer-coated reservoirs ordrug-polymer matrix formulations. Examples of controlled release systemsare given in U.S. Pat. Nos. 3,845,770 and 4,326,525 and in P. J. Kuzmaet al, Regional Anesthesia 22 (6): 543-551 (1997), all of which areincorporated herein by reference.

The compositions of the invention can also be delivered throughintra-nasal drug delivery systems for local, systemic, and nose-to-brainmedical therapies. Controlled Particle Dispersion (CPD)TM technology,traditional nasal spray bottles, inhalers or nebulizers are known bythose skilled in the art to provide effective local and systemicdelivery of drugs by targeting the olfactory region and paranasalsinuses.

The invention also relates to an intravaginal shell or core drugdelivery device suitable for administration to the human or animalfemale. The device may be comprised of the active pharmaceuticalingredient in a polymer matrix, surrounded by a sheath, and capable ofreleasing the compound in a substantially zero order pattern on a dailybasis similar to devises used to apply testosterone as desscribed in PCTPatent No. WO 98/50016.

Current methods for ocular delivery include topical administration (eyedrops), subconjunctival injections, periocular injections, intravitrealinjections, surgical implants and iontophoresis (uses a small electricalcurrent to transport ionized drugs into and through body tissues) Thoseskilled in the art would combine the best suited excipients with thecompound for safe and effective intra-occular administration.

The most suitable route will depend on the nature and severity of thecondition being treated. Those skilled in the art are also familiar withdetermining administration methods (oral, intravenous, inhalation,sub-cutaneous, rectal etc.), dosage forms, suitable pharmaceuticalexcipients and other matters relevant to the delivery of the compoundsto a subject in need thereof.

COMBINATION THERAPY

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of sodiumchannel-mediated diseases and conditions. For example, a compound offormula (I) may be administered simultaneously, sequentially orseparately in combination with other therapeutic agents, including, butnot limited to:

-   -   opiates analgesics, e.g. morphine, heroin, cocaine, oxymorphine,        levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,        propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone,        meripidine, methadone, nalorphine, naloxone, naltrexone,        buprenorphine, butorphanol, nalbuphine and pentazocine;    -   non-opiate analgesics, e.g. acetomeniphen, salicylates (e.g.        aspirin);    -   nonsteroidal antiinflammatory drugs (NSAIDs), e.g. ibuprofen,        naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac,        diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,        flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,        meclofenamic acid, mefenamic acid, meloxicam, nabumetone,        naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin,        phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and        zomepirac;    -   anticonvulsants, e.g. carbamazepine, oxcarbazepine, lamotrigine,        valproate, topiramate, gabapentin and pregabalin;    -   antidepressants such as tricyclic antidepressants, e.g.        amitriptyline, clomipramine, despramine, imipramine and        nortriptyline;,    -   COX-2 selective inhibitors, e.g. celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;    -   alpha-adrenergics, e.g. doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, and        4-amino-6,7-dimethoxy-2-(5-methane        sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;    -   barbiturate sedatives, e.g. amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal and thiopental;    -   tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1        antagonist, e.g.        (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[2R,3S)-2-[(1R)-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);    -   coal-tar analgesics, in particular paracetamol;    -   serotonin reuptake inhibitors, e.g. paroxetine, sertraline,        norfluoxetine (fluoxetine desmethyl metabolite), metabolite        demethylsertraline, '3 fluvoxamine, paroxetine, citalopram,        citalopram metabolite desmethylcitalopram, escitalopram,        d,I-fenfluramine, femoxetine, ifoxetine, cyanodothiepin,        litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and        fluoxetine;    -   noradrenaline (norepinephrine) reuptake inhibitors, e.g.        maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,        tomoxetine, mianserin, buproprion, buproprion metabolite        hydroxybuproprion, nomifensine and viloxazine (Vivalan®)),        especially a selective noradrenaline reuptake inhibitor such as        reboxetine, in particular (S,S)-reboxetine, and venlafaxine        duloxetine neuroleptics sedative/anxiolytics;    -   dual serotonin-noradrenaline reuptake inhibitors, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   acetylcholinesterase inhibitors such as donepezil;    -   5-HT3 antagonists such as ondansetron;    -   metabotropic glutamate receptor (mGluR) antagonists;    -   local anaesthetic such as mexiletine and lidocaine;    -   corticosteroid such as dexamethasone;    -   antiarrhythimics, e.g. mexiletine and phenytoin;    -   muscarinic antagonists, e.g., tolterodine, propiverine, tropsium        t chloride, darifenacin, solifenacin, temiverine and        ipratropium;    -   cannabinoids;    -   vanilloid receptor agonists (e.g. resinferatoxin) or antagonists        (e.g. capsazepine);    -   sedatives, e.g. glutethimide, meprobamate, methaqualone, and        dichloralphenazone;    -   anxiolytics such as benzodiazepines,    -   antidepressants such as mirtazapine,    -   topical agents (e.g. lidocaine, capsacin and resiniferotoxin);    -   muscle relaxants such as benzodiazepines, baclofen,        carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and        orphrenadine;    -   anti-histamines or H1 antagonists;    -   NMDA receptor antagonists;    -   5-HT receptor agonists/antagonists;    -   PDEV inhibitors;    -   Tramadol®;    -   cholinergic (nicotinc) analgesics;    -   alpha-2-delta ligands;    -   prostaglandin E2 subtype antagonists;    -   leukotriene B4 antagonists; and    -   5-lipoxygenase inhibitors.

Sodium channel-mediated diseases and conditions that may be treatedand/or prevented using such combinations include but not limited to,pain, central and peripherally mediated, acute, chronic, neuropathic aswell as other diseases with associated pain and other central nervousdisorders such as epilepsy, anxiety, depression and bipolar disease; orcardiovascular disorders such as arrhythmias, atrial fibrillation andventricular fibrillation; neuromuscular disorders such as restless legsyndrome and muscle paralysis or tetanus; neuroprotection againststroke, neural trauma and multiple sclerosis; and channelopathies suchas erythromyalgia and familial rectal pain syndrome.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

KITS-OF-PARTS

The present invention also provides kits that contain a pharmaceuticalcomposition which includes one or more compounds of the above formulae.The kit also includes instructions for the use of the pharmaceuticalcomposition for modulating the activity of ion channels, for thetreatment of pain, as well as other utilities as disclosed herein.Preferably, a commercial package will contain one or more unit doses ofthe pharmaceutical composition. For example, such a unit dose may be anamount sufficient for the preparation of an intravenous injection. Itwill be evident to those of ordinary skill in the art that compoundswhich are light and/or air sensitive may require special packagingand/or formulation. For example, packaging may be used which is opaqueto light, and/or sealed from contact with ambient air, and/or formulatedwith suitable coatings or excipients.

PREPARATION OF THE COMPOUNDS OF THE INVENTION

The following Reaction Schemes illustrate methods to make compounds ofthis invention, i.e., compounds of formula (I):

wherein k, j, Q, R¹, R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b),R^(3c), and R^(3d) are as defined herein, as a stereoisomer, enantiomer,tautomer thereof or mixtures thereof; or a pharmaceutically acceptablesalt, solvate or prodrug thereof.

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acid include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Protective Groups in Organic Synthesis (1999), 3rd Ed.,Wiley. The protecting group may also be a polymer resin such as a Wangresin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

The following Reaction Schemes illustrate methods to make compounds ofthis invention. It is understood that one skilled in the art would beable to make these compounds by similar methods or by methods known toone skilled in the art. It is also understood that one skilled in theart would be able to make in a similar manner as described below othercompounds of formula (I) not specifically illustrated below by using theappropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,e.g., Smith, M. B. and J. March, Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, 5th edition (Wiley, December 2000)) orprepared as described herein. In the following Reaction Schemes, R¹,R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) and R^(3d) aredefined as in the Specification unless specifically defined otherwise. Xis Cl or Br. R¹¹ is an alkyl group.

In general, the compounds of formula (I) of the invention where Q is—O—, j is 0 and k is 1 can be synthesized following the generalprocedure as described below in REACTION SCHEME 1. As set forth below,an isatin compound of formula (101) is alkylated with the chloro orbromo compound of formula (102) to afford the product of formula (103).The phenol compound of formula (104) is treated with a Grignard reagentof formula (105) at low temperature (0° C.) to form the phenoxymagnesiumhalide intermediate which reacts with the keto-carbonyl group of theisatin compound of formula (103) in a solvent, such as, but not limitedto, methylene chloride or toluene, to afford the oxindole of formula(106). The compound of formula (107) is obtained after the removal ofthe hydroxyl group at C-3 position of the oxindole by treating thecompound of formula (106) with silane such as triethylsilane. Thecompound of formula (107) can also be achieved by treating the compoundof formula (106) with SOCl₂/NEt₃ then reduction with Zn dust. Compoundof formula (107) is treated with a silyl compound, such as, but notlimited to, trimethylsilyl chloride, to generate the silyl etherintermediate which is treated with ytterbium (III)trifluoromethanesulfonate and formaldehyde to afford the compound offormula (108). Alternatively, compound of formula (108) can be obtainedby treating the compound of formula (107) with a base, such as, but notlimited to, LiOH, iPr₂NH, LDA, and subsequently reacting withformaldehyde. Intramolecular cyclization via Mitsunobu reaction affordsthe compound of formula (I) of the invention where Q is —O—, j is 0 andk is 1.

REACTION SCHEME 1.1 below illustrates a schematic synthesis of amide andheterocyclic compounds as compounds of formula (I). When R¹ consists ofan ester group, a compound such as a compound of formula (109) (in whichA is alkyl or aralkyl) can be converted to the corresponding carboxylicacid compound of formula (110) by treatment of a compound of formula(109) with a base such as, but not limited to, lithium hydroxide, sodiumhydroxide or potassium hydroxide, in a mixed solvent such as, but notlimited to, tetrahydrofuran or methanol with water. The acid compound offormula (110) can be converted to a mixed anhydride, by treatment withiso-butyl chioroformate in the presence of a base such as, but notlimited to, N-methylmorpholine, or to the corresponding acid chloride,by treament with oxalyl chloride in the presence of catalytic amount ofN,N-dimethylformamide in a solvent such as, but not limited to, toluene,dichloromethane or chloroform. The mixed anhydride can react directlywith, or the acid chloride can react with, in the presence of a basesuch as, but not limited to, triethylamine or diisopropyl ethylamine, aprimary or secondary amine to form the amide compound of formula (111)as a compound of formula (I). The acid compound of formula (110) canreact with an aromatic diamine compound in a solvent such as, but notlimited to, toluene to form the benzimidazole compound of formula(111.1) as a compound of formula (I).

REACTION SCHEME 1.2 below illustrates a schematic synthesis of aminecompounds as compounds of formula (I). From compound (112), afterremoval of the protecting group (PG) such as, but not limited to,phthalimido or tert-butyloxycarbonyl, either the primary or secondaryamino compound of formula (113) can be formed. Reaction of the aminocompound of formula (113) with an acyl chloride in the presence of abase such as, but not limited to, triethylamine or diisopropylethylamine, in a solvent such as, but not limited to, toluene,dichloromethane or chloroform provides the amide compound of formula(114) as a compound of formula (I). Treatment of amino compound offormula (113) with an isocyanate in the presence of a base such as, butnot limited to, triethylamine or diisopropyl ethylamine, in a solventsuch as, but not limited to, dichloromethane or chloroform leads to theformation of the urea compound of formula (115) as a compound of formula(I). When the primary or secondary amino compound of formula (113) istreated with an aldehyde or a ketone in the presence of a reducing agentsuch as, but not limited to, sodium cyanoborohydride or sodiumtriacetoxyborohydride, in a solvent such as, but not limited to,dichloromethane, a high order functionalized amine (116) is produced asa compound of formula (I).

REACTION SCHEME 1.3 below illustrates a schematic synthesis of aminecompounds as compounds of formula (I). The alcohol compound of formula(118), upon removal of the protecting group in compound of formula(117), can be oxidized to the aldehyde compound of (119) by using anoxidant such as, but not limited to, pyridinium dichromate orDess-Martin's reagent. Similarly to the transformation of the compoundof formula (113) to the compound of formula (116) as illustrated inREACTION SCHEME 1.2, the amine compound of formula (120) can be obtainedas a compound of formula (I) through the reductive amination of thealdehyde compound of formula (119) with a primary or secondary amine.

REACTION SCHEME 1.4 below illustrates an alternative synthesis ofcompounds of formula (I) with the introduction of a variety of R¹groups. Compound of formula (121) where PG is a protecting group suchas, but not limited to, diphenylmethyl, can be synthesized through thesequence as shown in REACTION SCHEME 1 above. The protecting group canbe removed under a high pressure of hydrogen such as 60 psi to form theoxindole compound of formula (122). The formation of a compound offormula (I) can be achieved by alkylation of the compound of formula(122) with a halide reagent XR¹ (where X is chloro, bromo or iodo) inthe presence of a base such as, but not limited to, sodium hydride,sodium bis(trimethylsilyl)amide, and lithium hydroxide, in a solventsuch as, but not limited to, N,N-dimethylformamide, tetrahydrofuran,acetone or acetonitrile. Alternatively, reaction of compound of formula(122) with an alcohol under Mitsunobu reaction conditions in thepresence of a phosphine reagent such as, but not limited to,triphenylphosphine, tributylphosphine or trimethyl phosphine, andazadicarboxylate of diethyl, diisopropyl or di-tert-butyl in a solventsuch as, but not limited to, tetrahydrofuran, ethyl acetate ordichloromethane, provides the compound of formula (I). Alternatively,treatment of compound of formula (122) with a base such as, but notlimited to, sodium hydride or lithium hydroxide, followed by reactingwith an acyl chloride or anhydride, or with a sulfonyl chloride reagent,provides the corresponding acyl or sulfonyl (R¹) compound of formula (I)respectively.

When R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d) ofthe compound of formula (I) is a bromo or trifluoromethylsulfonyloxygroup, further derivatives can be synthesized as shown in REACTIONSCHEME 1.5 and REACTION SCHEME 1.6 below. The triflate compound can beobtained by treating the bromo compound with diborane in the presence ofa palladium catalyst followed by sequential oxidation with hydrogenperoxide/sodium hydroxide and reaction with trifluoromethanesulfonylanhydride. Compounds of formula (123) or (129) (with either a bromo or atrifluoromethylsulfonyloxy group for R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d)) can react with zinc cyanide ortributyltin cyanide and potassium cyanide in the presence of a palladiumcatalyst such as, but not limited to, palladium acetate ortris(dibenzylideneacetone)dipalladium(0), and a ligand such as, but notlimited to, tri(o-tolyl)phosphine, 1,1′-bis(diphenylphosphino)ferroceneor 2-(di-tert-butylphosphino)biphenyl in a solvent such as, but notlimited to, N,N-dimethylformamide or acetonitrile to provide the cyanocompounds of formula (124) or formula (130) as compounds of formula (I)(see Marcantonio, K. M., et al, Org. Lett. (2004), 6:3723-5 and Yang,C., et al, Org. Lett. (2004), 6:2837-40). Reaction of compounds offormula (123) or formula (129) (with either a bromo or atrifluoromethylsulfonyloxy group for R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b), R^(3c) or R^(3d)) with a primary or secondary amine inthe presence of a palladium catalyst such as, but not limited to,palladium acetate, tetrakis(triphenylphosphine)palladium(0), ortris(dibenzylideneacetone)dipalladium(0), under a pressure of carbonmonoxide in a solvent such as, but not limited to, N,N-dimethylformamideor acetonitrile leads to the formation of the amide compound of formula(125) or formula (131) as compounds of formula formula (I) (SeeTakahashi, T., et al, Tetrahedron Lett. (1999), 40:7843-6 and Schnyder,A., et al, J. Org. Chem. (2001), 66:4311-5). Under a typical Ullmanncoupling reaction conditions, compounds of formula (123) or formula(129) (with either bromo or trifluoromethylsulfonyloxy group for R^(2a),R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d)) can react witha phenol compound in the presence of a copper reagent such as, but notlimited to, copper iodide or copper bromide, a base such as, but notlimited to, cesium carbonate or potassium carbonate, an amino acid suchas, but not limited to, N,N-dimethylglycine, in a solvent such as, butnot limited to, dimethyl sulfoxide, dioxane or acetonitrile, to form thediaryl ether compounds of formula (126) or formula (132) as compounds offormula (I) (see Sawyer, J. S. Tetrahedron (2000), 56:5045-65 and Ma,D., et al, Org. Lett. (2003), 5(21):3799-802). Compounds of formula(123) or formula (129) (with either bromo or trifluoromethylsulfonyloxygroup for R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b), R^(3c) orR^(3d)) can react with an arylboronic acid in the presence of apalladium catalyst such as, but not limited to, palladium acetate,tetrakis(triphenylphosphine)palladium(0), ortris(dibenzylideneacetone)dipalladium(0), with or without a ligand suchas, but not limited to, triphenylphosphine, tri(o-tolyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene or2-(di-tert-butylphosphino)biphenyl, a base such as, but not limited to,sodium carbonate, cesium carbonate, or sodium bicarbonate, in a solventsuch as, but not limited to, dimethoxyethane, dioxane, ortetrahedrofuran to provide the coupled product of formula (127) orformula (133) as compounds of formula (I) (see Kotha, S., et al,Tetrahedron (2002), 58:9633 and Miyaura, N., et al, Chem. Rev. (1995),95:2457). Compound of formula (123) or formula (129) (with either abromo or a trifluoromethylsulfonyloxy group for R^(2a), R^(2b), R^(2c),R^(2d), R^(3a), R^(3b), R^(3c) or R^(3d)) can react with a primary orsecondary amine in the presence of a palladium catalyst such as, but notlimited to, tetrakis(triphenylphosphine)palladium(0) ortris(dibenzylideneacetone)dipalladium(0), with or without a ligand suchas, but not limited to, triphenylphosphine, tri(o-tolyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene or2-(di-tert-butylphosphino)biphenyl, a base such as, but not limited to,sodium carbonate, cesium carbonate or sodium tert-butoxide, in a solventsuch as, but not limited to, dioxane or tetrahedrofuran, to provide theamino compound of formula (128) or formula (134) as compounds of formula(I) (see Muci, A. R., et al, Topics in Current Chemistry (2002),219:131).

Alternatively, the compound of formula (I) of the invention where Q is—O and k is 1 can be synthesized following the general procedure asdescribed below in REACTION SCHEME 2. As set forth below, a compound offormula (201) is treated with a lithium reagent of formula (202), suchas, but not limited to, n-BuLi at low temperature followed by thereaction with keto-carbonyl group of the isatin compound of formula(103) in a solvent, such as, but not limited to, THF to afford theoxindole of formula (203). The compound of formula (204) is obtainedafter the removal of the hydroxyl group at C-3 position of the oxindoleby treating the compound of formula (203) with silane such astriethylsilane. The compound of formula (204) can also be achieved bytreating the compound of formula (203) with SOCl₂/NEt₃ then reductionwith Zn dust. Compound of formula (204) is treated with a silylcompound, such as, but not limited to, trimethylsilyl chloride togenerate the silyl ether intermediate which is treated with ytterbium(III) trifluoromethanesulfonate and formaldehyde to afford the compoundof formula (205). Alternatively, a compound of formula (205) can beobtained by treating the compound of formula (204) with a base, such as,but not limited to, LiOH, iPr₂NH, or LDA, and subsequently reacting withformaldehyde. Intramolecular cyclization via Mitsunobu reaction affordsthe compound of formula (I) of the invention where Q is —O— and k is 1.

Alternatively, the compound of formula (I) of the invention where Q is—O— or —S— and k is 0 can be synthesized following the general procedureas described below in REACTION SCHEME 3 wherein intramolecularcyclization of the compound of formula (203) via Mitsunobu reactionaffords the compound of formula (I) of the invention where Q is —O— or—S— and k is 0.

Alternatively, the compound of formula (I) of the invention where Q is—C(O)—, —(CH₂)— or —(CF₂)— and j is 0 can be synthesized following thegeneral procedure as described in REACTION SCHEME 4. As set forth below,the Grignard reagent of formula (401) reacts with keto-carbonyl group ofthe isatin compound of formula (103) in a solvent, such as, but notlimited to, methylene chloride or toluene to afford the oxindole offormula (402). The compound of formula (403) is obtained after theremoval of the hydroxyl group at C-3 position of the oxindole bytreating the compound of formula (402) with silane such astriethylsilane. The compound of formula (403) can also be achieved bytreating the compound of formula (402) with SOCl₂/NEt₃, followed byreduction with Zn dust. Compound of formula (403) is alkylated at C-3position of oxindole ring with a compound of formula (404) to afford thecompound of formula (405) which is subjected to saponification togenerate the carboxylic acid of formula (406). This carboxylic acid isthen converted to an acid chloride of formula (407) following proceduresknown to one skilled in the art. Intramolecular cyclization in thepresence of an Lewis acid, such as, but not limited to, tin(IV)chloride, yields the compound of formula (I) of the invention where Q is—C(O)— and j is 0. The removal of the carbonyl group of the compound offormula (I) using a silane, such as triethylsilane, or other reagentsknown to the one skilled in the art, yields the compound of formula (I)of the invention where Q is —CH₂— and j is 0. Reaction of the carbonylgroup of the compound (408) of formula (I) with a fluorinating reagentsuch as, but not limited to, bis(2-methoxyethyl)aminosulfur trifluorideleads to the formation of di-fluoro compound of formula (I) of theinvention where Q is —CF₂— and j is 0. Reduction of the carbonyl groupof the compound (408) of formula (I) with a reducing agent such as, butnot limited to, sodium borohydride provides the hydroxy compound offormula (I) of the invention where Q is —CH(OH)— and j is 0. Furtheralkylation of the hydroxy compound of formula (I) by the method known toone skilled in the art gives the alkylated compound of formula (I) ofthe invention where Q is —CH(OR⁵)— and i is 0.

Alternatively, the compound of formula (I) of the invention where Q is—O—, j is 0 and k is 1 can be synthesized following the generalprocedure as described below in REACTION SCHEME 5. As set forth below,the phenol compound of formula (104) is treated with a Grignard reagentof formula (105) at low temperature (0° C.) to form the phenoxymagnesiumhalide intermediate which reacts with the keto-carbonyl group of theisatin compound of formula (101) in a solvent, such as, but not limitedto, tetrahedrofuran, methylene chloride or toluene, to afford theheterocyclic compound of formula (501). The compound of formula (502)can be obtained after the removal of the hydroxyl group of theheterocyclic compound by treating the compound of formula (501) with asilane such as triethylsilane. The compound of formula (502) can also beachieved by treating the compound of formula (501) with SOCl₂/NEt₃followed by reduction with Zn dust. Compound of formula (502) is treatedwith a silyl compound such as, but not limited to, trimethylsilylchloride, to generate the silyl ether intermediate which is treated withytterbium (III) trifluoromethanesulfonate and formaldehyde to afford thecompound of formula (503). Alternatively, compound of formula (503) canbe obtained by treating the compound of formula (502) with a base suchas, but not limited to, LiOH, iPr₂NH, or LDA, and by subsequentlyreacting with formaldehyde. Intramolecular cyclization via Mitsunobureaction affords the compound of formula (504) which can be alkylatedwith a chloro or bromo compound of formula (102) to afford the compoundof formula (I) of the invention where Q is —O—, j is 0 and k is 1.

Alternatively, the compound of formula (I) of the invention where Q is—NHC(O)—, j is 0 can be synthesized following the general procedure asdescribed below in REACTION SCHEME 6. As set forth below, treatment ofthe ketone compound (408) with an azide such as, but not limited to,sodium azide in an acid such as, but not limited to, trifluoroaceticacid provides the Schmidt reaction product of formula (I) of theinvention where Q is —NHC(O)—, j is 0.

Alternatively, the compound of formula (I) of the invention where Q is—C(O)O—, j is 0 can be synthesized following the general procedure asdescribed below in REACTION SCHEME 7. As set forth below, treatment ofthe compound of formula (701), which can be obtained following a similarprocedure as for the synthesis of compound of formula (405) as describedin REACTION SCHEME 4, with a base such as, but not limited to, lithiumhydroxide, sodium hydroxide or potassium hydroxide, in a mixed solventsuch as, but not limited to, tetrahydrofuran or methanol with water,leads to the formation of the lactone product of formula (I) of theinvention where Q is —C(O)O—, j is 0.

In the following Preparations, which are directed to intermediates usedin the preparation of the compounds of formula (I), and in the followingExamples, which are directed to compounds of formula (I), the compoundnumbers presented therein do not correspond to the compound numbers inthe above REACTION SCHEMES.

Preparation 1 Synthesis of4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of 4-bromo-1-pentyl-1H-indole

To a mixture of sodium hydride (2.54 g, 66.3 mmol, 60% dispersion inmineral oil) in anhydrous N,N-dimethylformamide (50.0 mL) was added4-bromoindole (10.0 g, 51.0 mmol) at 0° C. The reaction mixture wasstirred for 0.5 h followed by the addition of 1-bromopentane (9.25 g,61.2 mmol) at 0° C. The reaction mixture was stirred at ambienttemperature for 6 h and quenched with brine solution (20.0 mL). Thereaction mixture was diluted with water (100 mL) and extracted withether (3×200 mL). The combined organic layers was washed with brine (100mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography eluting with hexane (100%) to give the title compound(13.3 g, 98%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.27 (m,2H), 7.14 (t, 1H), 6.88 (t, 1H), 6.55 (d, 1H), 4.08 (t, 2H), 1.87-1.77(m, 2H), 1.39-1.22 (m, 4H), 0.89 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ136.3, 129.2, 128.4, 122.2, 122.1, 114.9, 108.7, 101.3, 46.8, 29.9,29.1, 22.3, 13.9.

B. Synthesis of 4-bromo-1-pentyl-1H-indole-2,3-dione

To a solution of 4-bromo-1-pentyl-1H-indole (25.0 g, 93.9 mmol) inanhydrous dimethylsulfoxide (350 mL) was added N-bromosuccinimide (50.2g, 282 mmol) in portions over 30 min. The reaction mixture was heated at60° C. for 3 h, upon which time the internal temperature increased to120° C. After cooling down to ambient temperature, the reaction mixturewas poured onto ethyl acetate/water (1/1, 600 mL). The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (3×500mL). The combined organic layers was washed with water (3×500 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness to yield the title compound (25.7 g,92%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.38 (t, 1H), 7.21 (t,1H), 6.82 (d, 1H), 3.68 (t, 2H), 1.72-1.59 (m, 2H), 1.39-1.25 (m, 4H),0.86 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 180.9, 157.2, 152.6, 138.4,128.3, 121.7, 116.3, 108.9, 40.4, 28.9, 26.9, 22.3, 13.9.

C. Synthesis of4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of 1,3-benzodioxol-5-ol (12.8 g, 92.9 mmol) intetrahydrofuran (200 mL) was added isopropylmagnesium chloride solution(50.7 mL, 101 mmol, 2.0 M in ether) at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h, upon which time the colorless precipitatewas formed. After the solvent was removed under reduced pressure, theresidue was dissolved in methylene chloride (100 mL) and added to asolution of 4-bromo-1-pentyl-1H-indole-2,3-dione (25.0 g, 84.5 mmol) indichloromethane (100 mL) via a canula over 10 min at 0° C. The reactionmixture was stirred at ambient temperature for 16 h, quenched withsaturated ammonium chloride solution (100 mL) and the organic layer wasseparated. The aqueous layer was extracted with dichloromethane (100mL). The combined organic layers was washed with brine, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatographyeluting with ethyl acetate-hexane to give the title compound (34.9 g,97%) as a brown gummy material: ¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (s,1H), 7.29-7.21 (m, 2H), 6.88-6.81 (m, 1H), 6.55, (s, 1H), 6.14 (s, 1H),5.86 (dd, 2H), 4.24 (s, 1H), 3.70-3.52 (m, 2H), 1.69-1.55 (m, 2H),1.31-1.24 (m, 4H), 0.83 (t, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.6,152.6, 149.1, 144.8, 141.2, 131.7, 127.7, 127.6, 121.0, 113.8, 108.3,106.7, 101.7, 101.4, 80.5 40.5, 28.8, 26.7 22.2, 13.9.

D. Synthesis of4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one(34.9 g, 80.4 mmol) in dichloromethane (100 mL) was addedtrifluoroacetic acid (18.7 g, 161 mmol) and triethylsilane (18.3 g, 161mmol). The brown solution was stirred at ambient temperature for 3 h andconcentrated in vacuo to dryness. The residue was diluted withdichloromethane (200 mL), washed with saturated ammonium chloridesolution (50.0 mL), brine (3×50.0 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was crystallized from ether to give the title compound (16.5g, 49%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 7.29-7.21 (m, 2H),7.14 (dd, 1H), 6.58 (s, 1H), 6.10 (s, 1H), 5.85 (dd, 2H), 5.01 (s, 1H),3.75-3.55 (m, 2H), 1.69-1.56 (m, 2H), 1.35-1.21 (m, 4H), 0.86 (t, 3H);¹³C NMR (75 MHz, CDCl₃) δ 177.9, 150.9, 147.6, 145.4, 141.6, 130.3 127.1126.8, 120.8, 113.3 108.0, 106.7, 101.5, 101.2, 59.9, 48.6, 40.7, 28.9,26.9, 22.3 13.9; MS (ES+) m/z 418.3 (M+1), 420.3 (M+1).

E. Synthesis of4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one(7.50 g, 17.9 mmol) in dry dichloromethane (150 mL) was addedtriethylamine (10.9 g, 108 mmol) and chlorotrimethylsilane (7.80 g, 71.8mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h anddiluted with dichloromethane (100 mL). The mixture was washed with water(3×50.0 mL), dried over anhydrous magnesium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was dissolvedin THF (150 mL) followed by the additions of formaldehyde solution (4.90mL, 179 mmol, 37 wt % in water) and ytterbium (III)trifluoromethanesulfonate (1.11 g, 1.79 mmol). The resulting mixture wasstirred at ambient temperature for 36 h. After the solvent was removedunder reduced pressure, the residue was diluted with dichloromethane(200 mL), washed with saturated sodium bicarbonate (50.0 mL), saturatedammonium chloride (50.0 mL) and water (100 mL). The organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness to yield the title compound (6.32 g,79%) as a fluffy solid: ¹H NMR (300 MHz, CDCl₃) δ 8.28 (s, 1H), 7.10 (t,1H), 7.00 (dd, 1H), 6.89 (dd, 1H), 6.83 (s, 1H), 6.27 (s, 1H), 6.85 (dd,2H), 4.52-4.41 (m, 2H), 3.90 (dd, 1H), 3.70-3.65 (m, 2H), 1.68-1.57 (m,2H), 1.36-1.29 (m, 4H), 0.83 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.1,150.3, 147.2, 147.2, 140.5, 129.6, 129.2, 125.6, 118.4, 114.8, 109.2,106.9, 101.0, 98.2, 62.6, 57.6, 39.9, 28.9, 26.7, 22.2, 13.5.

Preparation 2 Synthesis of1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(2-cyclopropylethyl)-1H-indole-2,3-dione

To a suspension of sodium hydride (1.61 g, 41.9 mmol, 60% dispersion inmineral oil) in anhydrous N,N-dimethylformamide (25.0 mL) was addedisatin (6.17 g, 41.9 mmol) at 0° C. The reaction mixture was stirred for0.5 h followed by the addition of (2-bromoethyl)cyclopropane (Maercker,A., et al, Justus Liebigs Ann. Chem. (1972), 759:132-157) (9.25 g, 61.2mmol). The resulting mixture was stirred at ambient temperature for 16 hand quenched with water (50.0 mL). The mixture was extracted with ethylacetate (3×100 mL). The combined organic layers was washed with water(3×50.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness to yield the titlecompound (6.50 g, 90%) as a viscous gum: ¹H NMR (300 MHz, CDCl₃) δ7.57-7.51 (m, 2H), 7.05 (t, 1H), 6.88 (d, 1H), 3.79-3.74 (m, 2H),1.59-1.52 (m, 2H), 0.70-0.61 (m, 1H), 0.44-0.38 (m, 2H), 0.05-0.02 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 183.7, 158.2, 151.2, 138.4, 125.4, 123.6,117.5, 110.3, 40.3, 32.2, 8.6, 4.3.

B. Synthesis of1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

To a solution of 1,3-benzodioxol-5-ol (1.25 g, 9.06 mmol) in THF (20.0mL) was added dropwise a solution of isopropylmagnesium chloridesolution (4.53 mL, 9.06 mmol, 2.0 M in THF) at 0° C. over 5 min. Thereaction mixture was stirred for 0.5 h upon which time colorlessprecipitate was formed. After the solvent was removed under reducedpressure, the residue was dissolved in dichloromethane (20.0 mL) andcooled to 0° C. A solution of 1-(2-cyclopropylethyl)-1H-indole-2,3-dione(1.77 g, 8.23 mmol) in dichloromethane (20.0 mL) was added to the abovesolution at 0° C. The resulting mixture was stirred at ambienttemperature for 16 h and quenched with saturated ammonium chloridesolution (30.0 mL). The organic layer was separated and washed withwater (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue wascrystallized from ethyl acetate and ether to give the title compound(2.22 g, 76%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.52 (s,1H), 7.46 (d, 1H), 7.37 (dt, 1H), 7.18 (dt, 1H), 6.90 (d, 1H), 6.56 (s,1H), 6.23 (s, 1H), 5.84 (dd, 2H), 4.55 (s, 1H), 3.87-3.63 (m, 2H),1.64-1.44 (m, 2H), 0.68-0.55 (m, 1H), 0.41-0.27 (m, 2H), −0.02-(−0.07)(m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 179.1, 152.4, 148.8, 142.7, 141.3,130.3, 129.1, 126.3, 123.7, 117.3, 109.5, 106.9, 101.9, 101.4, 79.3,40.6, 32.2, 8.6, 4.3, 4.2; MS (ES+) m/z 337.6 (M−17).

C. Synthesis of1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

To a solution of1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(2.22 g, 6.27 mmol) in dichloromethane (30.0 mL) was addedtrifluoroacetic acid (2.12 g, 18.8 mmol) and triethylsilane (2.14 g,18.8 mmol). The brown solution was stirred at ambient temperature for0.5 h and concentrated in vacuo to dryness. The residue was diluted withdichloromethane (100 mL), washed with water (3×50.0 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatographyeluting with ethyl acetate/hexane (20/80) to give the title compound(1.69 g, 80%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 9.21-9.10 (br,1H), 7.38-7.30 (m, 2H), 7.16 (t, 1H), 6.96 (d, 1H), 6.63 (s, 1H), 6.33(s, 1H), 5.84 (dd, 2H), 5.01 (s, 1H), 3.87-3.72 (m, 2H), 1.66-1.46 (m,2H), 0.69-0.59 (m, 1H), 0.43-0.30 (m, 2H), 0.09-0.06 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ 178.8, 151.3, 147.6, 144.1, 141.5, 128.7, 126.2,123.1, 115.2, 109.5, 109.4, 106.5, 101.5, 101.2, 47.4, 40.5, 32.2, 8.6,4.3, 4.2; MS (ES+) m/z 338.3 (M+1).

D. Synthesis of1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, makingvariations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (53%): R_(f)=0.28 (EtOAc/Hexanes, 1/1).

Preparation 3 Synthesis of ethyl[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane with ethylbromoacetate, the title compound was obtained (79%) as a light yellowpowder: ¹H NMR (300 MHz, CDCl₃) δ 7.64-7.54 (m, 2H), 7.16-7.11 (m, 1H),6.77 (d, 1H), 4.47 (s, 2H), 4.22 (q, 2H), 1.26 (t, 3H); MS(ES+) m/z256.2 (M+23).

B. Synthesis of ethyl[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, the title compound wasobtained (95%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.08 (s, 1H), 7.21-7.13 (m,2H), 6.93-6.86 (m, 3H), 6.57 (s, 1H), 6.19 (s, 1H), 5.88 (m, 2H), 4.47(m, 2H), 4.13 (q, 2H), 1.19 (t, 3H); MS (ES−) m/z 370.2 (M−1).

C. Synthesis of ethyl[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (84%) as a white powder: ¹H NMR (300MHz, DMSO-d₆) δ 9.37 (s, 1H), 7.19 (m, 1H), 7.01-6.90 (m, 3H), 6.43 (s,2H), 5.84 (m, 2H), 4.86 (s, 1H), 4.56 (s, 2H), 4.13 (q, 2H), 1.18 (t,3H); MS (ES+) m/z 378.2 (M+23).

D. Synthesis of ethyl[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained as a white powder: ¹H NMR (300 MHz,DMSO-d₆) δ 9.03 (s, 1H), 7.17-6.85 (m, 5H), 6.22 (s, 1H), 5.83 (s, 2H),5.04 (t, 1H), 4.56-4.08 (m, 5H), 3.69 (m, 1H), 1.18 (t, 3H); MS (ES+)m/z 408.1 (M+23).

Preparation 4 Synthesis of methyl3-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoateA. Synthesis of methyl3-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]benzoate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane withmethyl 3-(bromomethyl)benzoate, the title compound was obtained (84%) asa orange solid: ¹H NMR (300 MHz, CDCl₃) δ 7.99-7.95 (m, 2H), 7.60 (d,1H), 7.53-7.47 (m, 2H), 7.43 (d, 1H), 7.09 (t, 1H), 6.43 (d, 1H), 4.95(s, 2H), 3.89 (s, 3H).

B. Synthesis of methyl3-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with methyl3-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]benzoate, the titlecompound was obtained (96%): ¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 1H),7.92 (s, 1H), 7.85 (d, 1H), 7.41-7.38 (m, 1H), 7.32-7.24 (m, 2H),7.19-7.13 (m, 1H), 7.04-6.9 (m, 1H), 6.63 (d, 1H), 6.44 (s, 1H), 6.39(s, 1H), 5.79 (s, 2H), 5.05 (s, 1H), 4.83 (dd, 2H), 3.80 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 178.7, 167.0, 151.0, 148.5, 142.1, 141.1, 135.7,131.6, 130.5, 130.1, 129.1, 129.0, 128.4, 125.5, 123.9, 116.7, 109.7,106.5, 101.3, 100.5, 78.6, 60.6, 52.4, 43.6; MS (ES+) m/z 456.1 (M+23).

C. Synthesis of methyl3-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith methyl3-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate,the title compound was obtained (98%): MS (ES+) m/z 418.2 (M+1).

D. Synthesis of methyl3-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith methyl3-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate,the title compound was obtained (81%) as a white powder: MS (ES+) m/z470.3 (M+23), 448.3 (M+1).

Preparation 5 Synthesis of methyl4-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoateA. Synthesis of methyl4-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]benzoate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane withmethyl 4-(bromomethyl)benzoate, the title compound was obtained (84%) asan orange solid: ¹H-NMR (300 MHz, CDCl₃) δ 8.00 (d, 2H), 7.61 (d, 1H),7.46 (t, 1H), 7.38 (d, 2H), 7.09 (t, 1H), 6.69 (d, 1H), 4.96 (s, 2H),3.88 (s, 3H); MS (ES+) m/z 296.1 (M+1).

B. Synthesis of methyl4-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with methyl4-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]benzoate, the titlecompound was obtained (79%): MS (ES+) m/z 416.1 (M−17).

C. Synthesis of methyl4-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 2C, and making thevariations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith methyl4-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate,the title compound was obtained (98%) as a solid: MS (ES+) m/z 418.1(M+1).

D. Synthesis of methyl4-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith methyl4-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate,the title compound was obtained (81%): MS (ES+) m/z 448.1 (M+1).

Preparation 6 Synthesis of2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dioneA. Synthesis of1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane with2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione, the title compound wasobtained (92%): ¹H NMR (300 MHz, CDCl₃) δ 7.80-7.79 (m, 4H), 7.61-7.56(m, 1H), 7.49-7.46 (m, 1H), 7.18-7.16 (m, 1H), 7.07-7.05 (m, 1H),3.72-3.60 (m, 4H), 1.97-1.92 (m, 2H).

B. Synthesis of2-{3-[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-1H-indole-2,3-dione,the title compound was obtained (96%): ¹H NMR (300 MHz, CDCl₃) δ7.86-7.78 (m, 4H), 7.21-7.13 (m, 2H), 7.00-6.97 (m, 1H), 6.87-6.85 (m,2H), 6.15 (s, 1H), 5.86-5.84 (m, 2H), 3.69-3.65 (m, 4H), 2.46-2.45 (m,1H), 1.94-1.87 (m, 2H); MS (ES+) m/z 473.4 (M−17).

C. Synthesis of2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith2-{3-[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione,the title compound was obtained (94%): ¹H NMR (300 MHz, CDCl₃,) δ7.81-7.78 (m, 2H), 7.70-7.67 (m, 2H), 7.32-7.27 (m, 2H), 7.12-7.07 (m,1H), 6.90-6.87 (m, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 5.86 (dd, 2H), 4.82(s, 1H), 3.96-3.66 (m, 4H), 2.17-2.04 (m, 2H); MS (ES+) m/z 457.0 (M+1).

D. Synthesis of2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione,the title compound was obtained (94%) as a foam solid: ¹H NMR (300 MHz,CDCl₃) δ 9.20 (s, 1H), 7.81-7.79 (m, 2H), 7.68-7.61 (m, 2H), 7.35-7.25(m, 2H), 7.16-7.14 (m, 1H), 6.90 (d, 1H), 6.80 (s, 1H), 6.48 (s, 1H),5.86 (dd, 2H), 4.64 (d, 1H), 3.67-4.13 (m, 5H), 2.18-2.05-(m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 180.6, 168.6, 151.2, 147.8, 143.2, 141.2, 134.2,134.2, 131.9, 130.0, 128.7, 125.1, 123.2, 113.9, 108.7, 108.3, 101.3,100.6, 64.9, 58.0, 37.6, 36.1, 26.5; MS (ES+) m/z 487.3 (M+1).

Preparation 7 Synthesis of2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dioneA. Synthesis of1-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane with2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione, the title compound wasobtained (75%): ¹H NMR (300 MHz, CDCl₃) δ 7.85-7.78 (m, 4H), 7.65 (td,1H), 7.55 (dd, 1H), 7.25(d, 1H), 7.12 (t, 1H), 4.00-3.80 (m, 4H); MS(ES+) m/z 321 (M+1), 343 (M+23).

B. Synthesis of2-{2-[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indole-2,3-dione,the title compound was obtained (99%): ¹H NMR (300 MHz, CD₃OD) δ7.85-7.68 (m, 4H), 7.29 (td, 1H), 7.18-6.96 (m, 3H), 6.88 (s, 1H), 6.16(s, 1H), 5.85 (s, 1H), 5.82 (s, 1H), 3.81-4.01 (m, 4H); MS (ES+) m/z 441(M−17), 458 (M+23).

C. Synthesis of2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith2-{2-[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione,the title compound was obtained (90%) as a white solid: ¹H NMR (300 MHz,CD₃OD) δ 10.15-10.05 (br, 1H), 8.66-8.58 (m, 4H), 8.07-7.70 (m, 4H),7.12 (s, 1H), 7.18 (s, 1H), 6.70 (s, 1H), 6.69 (s, 1H), 5.50 (s, 1H),4.91-4.56 (m, 4H); MS (ES+) m/z 443 (M+1).

D. Synthesis of2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione

Following the procedure as described in PREPARATION 1E, making variationto replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione,the title compound was obtained (56%): ¹H NMR (300 MHz, CD₃OD) δ 9.97(s, 1H), 8.72-8.62 (m, 4H), 8.07-7.67 (m, 5H), 7.01 (s, 1H), 6.71 (s,1H), 6.70 (s, 1H), 5.79 (t, 1H), 4.88-4.50 (m, 6H); MS (ES+) m/z 455(M−17), 473 (M+1), 495 (M+23).

Preparation 8 Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane with1,1′-(bromomethylene)dibenzene, the title compound was obtained (68%) asan orange solid: MS (ES+) m/z 336.4 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-(diphenylmethyl)-1H-indole-2,3-dione, the title compound was obtained(99%) as an off-white powder: MS (ES+) m/z 474.5 (M+23).

C. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and making thevariations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (84%) as an off-white solid: MS (ES+)m/z 458.4 (M+23).

D. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations using1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-oneto replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (56%): MS (ES+) m/z 488.3 (M+23).

Preparation 9 Synthesis of1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-[3-(benzyloxy)propyl]-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 1A, and makingnon-critical variations to replace 4-bromoindole with isatin, and1-bromopentane with benzyl 3-bromopropyl ether, the title compound wasobtained (95%) as a pale yellow syrup: ¹H NMR (300 MHz, CDCl₃) δ7.57-6.92 (m, 9H), 4.50 (s, 2H), 3.84 (t, 2H), 3.54 (t, 2H), 2.03-1.94(m, 2H); MS (ES⁺) m/z 296.3 (M+1), 318.3 (M+23).

B. Synthesis of1-[3-(benzyloxy)propyl]-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-[3-(benzyloxy)propyl]-1H-indole-2,3-dione, the title compound wasobtained (70%): ¹H NMR (300 MHz, CDCl₃) δ 9.42 (s, 1H), 7.32-7.16 (m,8H), 6.96 (d,), 6.61 (s, 1H), 6.23 (s, 1H), 5.86-5.83 (m, 2H), 4.44 (s,2H), 3.88-3.73(m, 2H), 3.46 (t, 2H), 2.06-1.85 (m, 2H); MS (ES+) m/z416.3 (M−17), 456.3 (M+23).

C. Synthesis of1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith1-[3-(benzyloxy)propyl]-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (92%): ¹H NMR (300 MHz, CDCl₃)δ7.42-6.95 (m, 9H), 6.56 (s, 1H), 6.24 (s, 1H), 5.86 (ABq, 1H),5.81(ABq, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.91-3.76 (m, 2H), 3.46 (t,2H), 2.03-1.93 (m, 2H); MS (ES+) m/z 418.3 (M+1).

D. Synthesis of1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (93%): MS (ES+) m/z 448.2 (M+1).

Preparation 10 Synthesis of methyl2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoateA. Synthesis of methyl2-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]benzoate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane withmethyl 2-(bromomethyl)benzoate, the title compound was obtained (68%) asa yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.05 (dd, 1H), 7.64 (dd, 1H),7.50-7.31 (m, 3H), 7.22 (d, 1H), 7.10 (t, 1H), 6.72 (d, 1H), 5.41 (s,2H), 3.95 (s, 3H).

B. Synthesis of methyl2-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with methyl2-[(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]benzoate, the titlecompound was obtained (97%) as a colorless solid: ¹H NMR (300 MHz,DMSO-d₆) δ 9.29 (s, 1H), 7.97 (dd, 1H), 7.53-7.36 (m, 3H), 7.28 (s, 1H),7.10 (td, 1H), 6.96-6.83 (m, 2H), 6.59 (d, 2H), 6.25 (s, 1H), 5.95-5.86(m, 2H), 5.31-5.07 (m, 2H), 3.88 (s, 3H); MS (ES+) m/z 456.1 (M+23).

C. Synthesis of methyl2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith methyl2-{[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate,the title compound was obtained (100%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 9.32 (s, 1H), 7.94 (dd, 1H), 7.50-7.34 (m, 2H), 7.26 (d,1H), 7.08 (t, 1H), 7.00-6.86 (m, 2H), 6.76 (s, 1H), 6.64 (d, 1H), 6.38(s, 1H), 5.93-5.86 (m, 2H), 5.34-5.12 (m, 2H), 4.83 (s, 1H), 3.87 (s,3H); MS (ES+) m/z 418.2 (M+1).

D. Synthesis of methyl2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate

A solution of methyl2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate(17.1 g, 40.0 mmol) and paraformaldehyde (10.3 g, 330 mmol) in THF (500mL) was degassed by bubbling through argon for 2 hours. To this solutionwas added lithium diisopropylamide solution (45.1 mL, 2 M solution, 90.0mmol) slowly at −78° C. The mixture was stirred at ambient temperatureovernight and quenched with saturated ammonium chloride solution. Themixture was concentrated in vacuo to remove THF followed by the additionof ethyl acetate (500 mL). The organic layer was washed with water,dried over sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was recrystallized from ethylacetate/hexanes to give the title compound (13.7 g, 75%): ¹H NMR (300MHz, DMSO-d₆) δ 9.20 (s, 1H), 7.95 (dd, 1H), 7.53-7.33 (m, 3H),7.08-6.82 (m, 4H), 6.53 (d, 1H), 6.25 (s, 1H), 5.93-5.86 (m, 2H),5.31-5.07 (m, 3H), 4.26-4.17 (m, 1H), 4.00-3.92 (m, 1H), 3.88 (s, 3H);MS (ES+) m/z 448.3 (M+1).

Preparation 11 Synthesis of[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]aceticacid A. Synthesis of 1-pentyl-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane with1-bromopentane, the title compound was obtained (85%) as an orangesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.52 (m, 2H), 7.08 (td, 1H), 6.87(d, 1H), 3.69 (t, 2H), 1.74-1.61 (m, 2H), 1.40-1.28 (m, 4H), 0.88 (t,3H).

B. Synthesis of3-(1,3-benzodioxol-5-yl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of 1-pentyl-1H-indole-2,3-dione (2.80 g, 12.8 mmol) in THF(50.0 mL) was added 3,4-(methylenedioxy)phenylmagnesium bromide (14.0mL, 1 M THF solution, 14.0 mmol) slowly at −78° C. The mixture wasstirred at 0° C. for 1 h and quenched with ammonium chloride solution.The mixture was poured into water (150 mL) and extracted with ethylacetate (200 mL). The organic layer was washed with water, dried oversodium sulfate and filtered. The filtrate was concentrated in vacuo todryness. The residue was subjected to flash column chromatography toafford the title compound (3.10 g, 71%) as an orange oil: ¹H NMR (300MHz, CDCl₃) δ 7.34-7.23 (m, 2H), 7.05 (t, 1H), 6.91-6.85 (m, 2H),6.83-6.78 (m, 1H), 6.71 (d, 1H), 5.92-5.89 (m, 2H), 3.82-3.55 (m, 2H),3.40 (br, 1H), 1.76-1.61 (m, 2H), 1.39-1.28 (m, 4H), 0.87 (t, 3H).

C. Synthesis of3-(1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith3-(1,3-benzodioxol-5-yl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (90%) as an oil: ¹H NMR (300 MHz, CDCl₃)δ 7.30 (td, 1H), 7.14 (d, 1H), 7.03 (td, 1H), 6.89 (d, 1H), 6.75 (d,1H), 6.67 (dd, 1H), 6.57 (d, 1H), 5.90 (s, 2H), 4.50 (s, 1H), 3.81-3.62(m, 2H), 1.76-1.62 (m, 2H), 1.41-1.28 (m, 4H), 0.88 (t, 3H); ¹³C NMR (75MHz, CDCl₃) δ 176.8, 148.1, 147.2, 143.5, 130.0, 129.4, 128.4, 125.1,122.9, 122.0, 108.7, 108.6, 101.1, 51.9, 40.4, 29.0, 27.1, 22.3, 14.0.

D. Synthesis of methyl[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetate

A solution of3-(1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one (1.00 g,3.10 mmol) and methyl bromoacetate (0.44 mL, 4.60 mmol) in THF (20.0 mL)was degassed by bubbling through argon for one hour. Sodium hydride(0.19 g, 4.60 mmol) was added at 0° C. The mixture was stirred at 0° C.for 1 h and quenched with ammonium chloride solution. The mixture waspoured into water (150 mL), and extracted with ethyl acetate (200 mL).The organic layer was washed with water, dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas subjected to flash column chromatography to afford the titlecompound (0.94 g, 76%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.30 (td, 1H), 7.25 (dd, 1H), 7.06 (td, 1H), 6.89 (d, 1H), 6.81 (d, 1H),6.74-6.65 (m, 2H), 5.90-5.87 (m, 2H), 3.71-3.64 (m, 2H), 3.45 (d, 1H),3.41 (s, 3H), 3.18 (d, 1H), 1.74-1.60 (m, 2H), 1.39-1.22 (m, 4H), 0.85(t, 3H); ¹³C NMR (75 MHz, CDCl₃,) δ 177.8, 170.0, 147.9, 147.0, 143.9,133.1, 131.3, 128.6, 124.6, 122.3, 119.9, 108.7, 108.1, 107.4, 101.2,52.8, 51.6, 41.8, 40.4, 29.0, 26.8, 22.3, 14.0; MS (ES+) m/z 418.1(M+23), 396.1 (M+1).

E. Synthesis of[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]aceticacid

To a solution of methyl[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetate(5.90 g, 15.0 mmol) in THF/water (2/1 v/v, 120 mL) was added lithiumhydroxide monohydrate (1.26 g, 28.0 mmol). The mixture was stirred atambient temperature overnight. Most THF was removed under vacuum andwater (150 mL) was added. The solution was extracted with ethylacetate/hexanes (1/3 v/v, 50.0 mL). The water layer was acidified with 1N HCl solution until the pH value reached 2 and extracted with ethylacetate (200 mL). The organic layer was washed with water, dried oversodium sulfate and filtered. The filtrate was concentrated in vacuo todryness to afford the title compound (5.00 g, 88%) as a white solid: ¹HNMR (300 MHz, CDCl₃) δ 7.29 (td, 1H), 7.21 (dd, 1H), 7.05 (td, 1H), 6.87(d, 1H), 6.76 (d, 1H), 6.72-6.64 (m, 2H), 5.90-5.86 (m, 2H), 3.65 (t,2H), 3.43 (d, 1H), 3.11 (d, 1H), 1.70-1.55 (m, 2H), 1.36-1.22 (m, 4H),0.85 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 174.0, 148.0, 147.1,143.4, 132.6, 131.4, 128.7, 124.4, 122.7, 119.8, 108.9, 108.2, 107.2,101.2, 52.6, 41.5, 40.4, 29.0, 26.6, 22.3, 14.0; MS (ES+) m/z 404.0(M+23), 382.0 (M+1).

Preparation 12 Synthesis of3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoicacid A. Synthesis of methyl3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoate

Following the procedure as described in PREPARATION 11D, and makingnon-critical variations to replace methyl bromoacetate with methyl3-bromopropionate, the title compound was obtained (76%) as a colorlessoil: ¹H NMR (300 MHz, CDCl₃) δ 7.28 (td, 1H), 7.17 (dd, 1H), 7.06 (td,1H), 6.89 (d, 1H), 6.84 (d, 1H), 6.77 (dd, 1H), 6.68 (d, 1H), 5.89-5.84(m, 2H), 3.67 (t, 2H), 3.53 (s, 3H), 2.69-2.56 (m, 1H), 2.54-2.41 (m,1H), 2.21-2.08 (m, 1H), 1.99-1.86 (m, 1H), 1.72-1.59 (m, 2H), 1.38-1.24(m, 4H), 0.85 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 173.1, 147.9,146.9, 143.2, 133.5, 131.6, 128.5, 124.9, 122.6, 120.1, 108.7, 108.1,107.6, 101.1, 55.2, 51.6, 40.2, 32.4, 29.5, 29.1, 27.1, 22.3, 14.0; MS(ES+) m/z 410.1 (M+1), 432.0 (M+23).

B. Synthesis of3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoicacid

Following the procedure as described in PREPARATION 11E, and makingnon-critical variations to replace methyl[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetatewith methyl3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoate,the title compound was obtained (92%) as a colorless solid: MS (ES−) m/z394.2 (M−1).

Preparation 13 Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with3,4-difluorophenol, the title compound was obtained (31%): ¹H NMR (300MHz, CDCl₃) δ 9.69-9.65 (br, 1H), 7.51-7.41 (m, 2H), 7.26-7.21 (m, 1H),6.99-6.57 (m, 3H), 4.18-4.14 (br, 1H), 3.78-3.58 (m, 2H), 1.76-1.62 (m,2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 330 (M−17), 370(M+23).

B. Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (98%): ¹H NMR (300 MHz, CDCl₃) δ7.46-7.19 (m, 3H), 7.03-6.68 (m, 3H), 5.03 (s, 1H), 3.76-3.67 (m, 2H),1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 332(M+1).

C. Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(4,5-difluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (96%): MS (ES+) m/z 344 (M−17), 384(M+23).

Preparation 14 Synthesis of3-(5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with4-fluorophenol, the title compound was obtained (53%): ¹H NMR (300 MHz,CDCl₃) δ 9.42-9.14 (br, 1H), 7.53-6.86 (m, 6H), 6.56-6.48 (m, 1H),4.58-4.28 (br, 1H), 3.79-3.58 (m, 2H), 1.77-1.61 (m, 2H), 1.41-1.24 (m,4H), 0.87 (t, 3H); MS (ES+) m/z 312 (M−17), 352 (M+23).

B. Synthesis of3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one(2.42 g, 7.35 mmol) in dichloromethane (10.0 mL) were addedtrifluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) at ambienttemperature. The reaction mixture was stirred at 40° C. for 15 hrs andconcentrated in vacuo to dryness. The residue was triturated with etherto give the title compound (2.10 g, 91%) as a solid: MS (ES+) m/z 314(M+1).

C. Synthesis of3-(5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one (2.10g, 6.70 mmol) in THF (20.0 mL) were added paraformaldehyde (1.76 g, 58.8mmol) and lithium diisopropylamide (7.35 mL, 2.0 M in THF, 14.7 mmol) at0° C. The reaction mixture was stirred at 0° C. for 2 hrs followed bythe addition of ammonium chloride solution (10.0 mL) and ethyl acetate(100 mL). The organic layer was washed with water and brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo to drynessto give the title compound: ¹H NMR (300 MHz, CDCl₃) δ 9.55-9.10 (br,1H), 7.53-6.86 (m, 6H), 6.57-6.49 (m, 1H), 4.74-4.30 (br, 1H), 4.18-4.07(m, 2H), 3.79-3.60 (m, 2H), 1.77-1.61 (m, 2H), 1.41-1.24 (m, 4H), 0.87(t, 3H); MS (ES+) m/z 326 (M−17), 366 (M+23).

Preparation 15 Synthesis of3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with4-bromophenol, the title compound was obtained (41%): ¹H NMR (300 MHz,CDCl₃) δ 9.46-9.25 (br, 1H), 7.51-6.80 (m, 7H), 4.73-4.51(br, 1H),3.79-3.56 (m, 2H), 1.76-1.60 (m, 2H), 1.41-1.22 (m, 4H), 0.87 (t, 3H);MS (ES+) m/z 377 (M−17), 379 (M−17), 412 (M+23), 414 (M+23).

B. Synthesis of3-(5-bromo-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one(2.22 g, 5.64 mmol) in dichloromethane (10.0 mL) were addedtrifluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) at ambienttemperature. The reaction mixture was stirred at 50° C. for 15 hrs andconcentrated in vacuo to dryness to give the title compound: MS (ES+)m/z 374 (M+1), 376 (M+1).

C. Synthesis of3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 14C, and makingnon-critical variations to replace3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one with3-(5-bromo-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, thetitle compound was obtained: MS (ES+) m/z 386 (M−17), 388 (M−17), 426(M+23), 428 (M+23).

Preparation 16 Synthesis of3-(5-chloro-4-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(5-chloro-4-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with4-chloro-3-fluorophenol, the title compound was obtained (33%): ¹H NMR(300 MHz, CDCl₃) δ 9.80 (s, 1H), 7.52-7.41 (m, 2H), 7.23 (t, 1H), 6.96(d, 1H), 6.84 (d, 1H), 6.80 (d, 1H), 4.15 (s, 1H), 3.79-3.58 (m, 2H),1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 346(M−17), 386 (M+23).

B. Synthesis of3-(5-chloro-4-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(5-chloro-4-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (99%): ¹H NMR (300 MHz, CDCl₃) δ10.0-9.70 (br, 1H), 7.45-7.18 (m, 3H), 6.98 (d, 1H), 6.90-6.82 (m, 2H),5.01 (s, 1H), 3.75-3.66 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H),0.87 (t, 3H); MS (ES+) m/z 348 (M+1).

C. Synthesis of3-(5-chloro-4-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(5-chloro-4-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (46%): MS (ES+) m/z 360 (M−17), 400(M+23).

Preparation 17 Synthesis of3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with3-chloro-4-fluorophenol, the title compound was obtained (14%): MS (ES+)m/z 346 (M−17), 386 (M+23).

B. Synthesis3-(4-chloro-5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 348 (M+1).

C. Synthesis of3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(4-chloro-5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (50% for two steps): MS (ES+) m/z 360(M−17), 400 (M+23).

Preparation 18 Synthesis of3-(4,5-dichloro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(4,5-dichloro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with3,4-dichlorophenol, the title compound was obtained (26%): ¹H NMR (300MHz, CDCl₃) δ 9.60 (s, 1H), 7.50-7.40 (m, 2H), 7.22 (td, 1H), 7.11 (s,1H), 6.95 (d, 1H), 6.86 (s, 1H), 4.31-4.12 (br, 1H), 3.79-3.59 (m, 2H),1.76-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 363(M−17), 403 (M+23).

B. Synthesis of3-(4,5-dichloro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(4,5-dichloro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (86%): ¹H NMR (300 MHz, CDCl₃) δ10.0-9.50 (br, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.22 (td, 1H), 7.09 (s,1H), 6.95 (d, 1H), 6.93 (s, 1H), 5.04(s, 1H), 3.77-3.68 (m, 2H),1.77-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 348(M+1).

C. Synthesis of3-(4,5-dichloro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(4,5-dichloro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 376 (M−17), 416 (M+23).

Preparation 19 Synthesis of3-(hydroxymethyl)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol withα,α,α-trifluorocresol, the title compound was obtained (46%): ¹H NMR(300 MHz, CDCl₃) δ 9.75 (s, 1H), 7.50-7.39 (m, 3H), 7.21 (td, 1H),7.10-7.02 (m, 2H), 6.96 (d, 1H), 4.26 (s, 1H), 3.82-3.59 (m, 2H),1.77-1.63 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 362(M−17), 402 (M+23).

B. Synthesis of3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (78%): ¹H NMR (300 MHz, CDCl₃) δ8.20-8.00 (br, 1H), 7.43-7.14 (m, 5H), 7.02 (d, 1H), 6.95 (d, 1H),5.11(s, 1H), 3.82-3.72 (m, 2H), 1.79-1.66 (m, 2H), 1.40-1.27 (m, 4H),0.88 (t, 3H); MS (ES+) m/z 364 (M+1).

C. Synthesis of3-(hydroxymethyl)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 376 (M−17), 416 (M+23).

Preparation 20 Synthesis of3-(2-hydroxy-4-methoxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(5-bromo-2-hydroxy-4-methoxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with4-bromo-3-methoxyphenol, the title compound was obtained (48%): ¹H NMR(300 MHz, CDCl₃) δ 9.85 (s, 1H), 7.52-7.38 (m, 2H), 7.22 (td, 1H), 6.94(d, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 4.13-4.03 (br, 1H), 3.86 (s, 3H),3.80-3.57 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.88 (t, 3H);MS (ES+) m/z 402 (M−17), 404 (M−17), 442 (M+23), 444 (M+23).

B. Synthesis of3-(2-hydroxy-4-methoxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(5-bromo-2-hydroxy-4-methoxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (83%): ¹H NMR (300 MHz, CDCl₃) δ9.78-9.20 (br, 1H), 7.43-7.31 (m, 2H), 7.19 (t, 1H), 6.97 (d, 1H), 6.79(d, 1H), 6.70-6.64 (m, 1H), 6.38 (dd, 1H), 5.02 (s, 1H), 3.77 (s, 3H),3.70 (t, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.87 (t, 3H); MS(ES+) m/z 326 (M+1).

C. Synthesis of3-(2-hydroxy-4-methoxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith 3-(2-hydroxy-4-methoxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (41%): ¹H NMR (300 MHz, CDCl₃) δ 10.79(s, 1H), 7.51-7.37 (m, 2H), 7.26 (td, 1H), 6.99 (d, 1H), 6.95 (d, 1H),6.59 (d, 1H), 6.34 (dd, 1H), 4.67 (d, 1H), 4.14 (d, 1H), 3.76 (s, 3H),3.78-3.69 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.87 (t, 3H);MS (ES+) m/z 338 (M−17), 378 (M+23).

Preparation 21 Synthesis of ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of ethyl[3-hydroxy-3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and1,3-benzodioxol-5-ol with 5-indanol, the title compound was obtained(84%): ¹H NMR (300 MHz, CDCl₃) δ 8.76 (s, 1H), 7.55 (d, 1H), 7.38 (td,1H), 7.20 (t, 1H), 6.9 (s, 1H), 6.80 (d, 1H), 6.65 (s, 1H), 4.45 (ABq,2H), 4.32-4.25 (br, 1H), 4.20 (q, 2H), 2.83 (t, 2H), 2.74-2.65 (m, 2H),2.06-1.94 (m, 2H), 1.27 (t, 3H); MS (ES+) m/z 350 (M−17), 390 (M+23).

B. Synthesis of ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[3-hydroxy-3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained: ¹H NMR (300 MHz, CDCl₃) δ 8.50-7.90(br, 1H), 7.40-7.32 (m, 2H), 7.38 (td, 1H), 6.94 (s, 1H), 6.84 (d, 1H),6.75 (s, 1H), 5.16 (s, 1H), 4.48 (ABq, 2H), 4.21 (q, 2H), 2.85 (t, 2H),2.81-2.61 (m, 2H), 2.09-1.92 (m, 2H), 1.25 (t, 3H); MS (ES+) m/z 352(M+1).

C. Synthesis of ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained: MS (ES+) m/z 364 (M−17), 404 (M+23).

Preparation 22 Synthesis of ethyl[3-(hydroxymethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of ethyl[3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and1,3-benzodioxol-5-ol with 5,6,7,8-tetrahydronapthalen-2-ol, the titlecompound was obtained (81%): ¹H NMR (300 MHz, CDCl₃) δ 8.61 (s, 1H),7.54 (dd, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.80 (d, 1H), 6.76 (s, 1H),6.50 (s, 1H), 4.45 (ABq, 2H), 4.21 (q, 2H), 4.18-4.14 (br, 1H),2.73-2.47 (m, 4H), 1.77-1.63 (m, 4H), 1.24 (t, 3H); MS (ES+) m/z 364(M−17), 404 (M+23)

B. Synthesis of ethyl[3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained: ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.32 (m,2H), 7.20 (t, 1H), 6.84 (d, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 5.12 (s,1H), 4.47 (ABq, 2H), 4.21 (q, 2H), 2.76-2.44 (m, 4H), 1.78-1.64 (m, 4H),1.24 (t, 3H); MS (ES+) m/z 366 (M+1).

C. Synthesis of ethyl[3-(hydroxymethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained: MS (ES+) m/z 378 (M−17), 418 (M+23).

Preparation 23 Synthesis of ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace isatin with 4-bromoisatin and(2-bromoethyl)cyclopropane with ethyl bromoacetate, the title compoundwas obtained as a yellow solid (68%): ¹H NMR (300 MHz, CDCl₃) δ 7.39 (t,1H), 7.27(dd, 1H), 6.71 (dd, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t,3H); MS (ES+) m/z 312 (M+1), 314 (M+1), 334 (M+23), 336 (M+23).

B. Synthesis of ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate and1,3-benzodioxol-5-ol with 3,4-difluorophenol, the title compound wasobtained as a white solid (42%); MS (ES+) m/z 424 (M−17), 426 (M−17),464 (M+23), 466 (M+23).

C. Synthesis of ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

A mixture of ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate(0.90 g, 2.00 mmol), triethylsilane (2.00 mL, 12.2 mmol) andtrifluoroacetic acid (0.94 mL, 12.2 mmol) was heated at 90° C. for twodays. After cooling down to ambient temperature, the mixture was dilutedwith ethyl acetate (200 mL), washed with water, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo todryness. The residue was subjected to column chromatography (ethylacetate/hexanes, 1/3) to give the title compound (0.37 g, 43%): ¹H NMR(300 MHz, CDCl₃) δ 7.35-7.22 (m, 3H), 6.82-6.71 (m, 2H), 6.52 (t, 1H),5.10 (s, 1H), 4.45 (s, 2H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES+) m/z426.4 (M+1), 428.4 (M+1).

D. Synthesis of ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (83%): MS (ES+) m/z 456.3 (M+1), 458.3(M+1).

Preparation 24 Synthesis of ethyl[4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of 6-(benzyloxy)-2,2-dimethylbenzofuran-3(2H)-one

To a solution of 6-(benzyloxy)benzofuran-3(2H)-one (Adams, J. L., etal., J. Med. Chem. (1996), 39(26):5035-46) (1.60 g, 6.67 mmol) in DMF(50.0 mL) were added sodium hydride (0.59 g, 14.7 mmol) and iodomethane(1.46 mL, 23.3 mmol) at 0° C. The reaction mixture was stirred atambient temperature for 16 h and quenched with saturated ammoniumchloride (50.0 mL). The aqueous mixture was extracted with ethyl acetate(3×50.0 mL). The combined organic layers was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to column chromatography (ethylacetate/hexane, 1/10) to give the title compound (0.85 g, 47%): ¹H NMR(300 MHz, CDCl₃) δ 7.55 (d, 1H), 7.44-7.30 (m, 5H), 6.69 (dd, 1H), 6.54(d, 1H), 5.10 (s, 2H), 1.43 (s, 6H); MS (ES+) m/z 269.5 (M+1).

B. Synthesis of 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol

To a solution of 6-(benzyloxy)-2,2-dimethylbenzofuran-3(2H)-one (0.85 g,3.20 mmol) in methanol (100 mL) was added palladium hydroxide (0.22 g,20 wt. % loading, 0.32 mmol). The resulting mixture was hydrogenated for16 hours under 60 psi of hydrogen. The reaction mixture was filteredthrough celite, washed with methanol. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatography(ethyl acetate/hexane, 1/5) to give the title compound (0.46 g, 88%): ¹HNMR (300 MHz, CDCl₃) δ 6.92 (d, 1H), 6.30-6.21 (m, 2H), 4.77 (s, 1H),2.90 (s, 2H), 1.44 (s, 6H).

C. Synthesis of ethyl[4-bromo-3-hydroxy-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate and1,3-benzodioxol-5-ol with 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol, thetitle compound was obtained: MS (ES+) m/z 498.5 (M+23), 500.5 (M+23).

D. Synthesis of ethyl[4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

A mixture of ethyl[4-bromo-3-hydroxy-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate(1.32 g, 2.80 mmol), triethylsilane (2.00 mL, 12.2 mmol) andtrifluoroacetic acid (0.94 mL, 12.2 mmol) in dichloromethane (50.0 mL)was stirred at 35° C. for 3 hours. The mixture was diluted withdichloromethane (100 mL), washed with water, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to column chromatography (ethylacetate/hexane, 1/3) to give the title compound (1.04 g, 81%): ¹H NMR(300 MHz, CDCl₃) δ 7.32-7.15 (m, 2H), 6.74 (d, 1H), 6.50-6.36 (br, 2H),5.04 (s, 1H), 4.51-4.34 (m, 2H), 4.25-4.14 (m, 2H), 2.92-2.69 (m, 2H),1.43 (s, 3H), 1.37 (s, 3H), 1.23 (t, 3H); MS (ES+) m/z 460.5 (M+1),462.5 (M+1).

E. Synthesis of ethyl[4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (25%): MS (ES+) m/z 490.5 (M+1), 492.5(M+1).

Preparation 25 Synthesis of 3,3-dimethyl-2,3-dihydro-1-benzofuran-6-olA. Synthesis of 4-(benzyloxy)-1-bromo-2-(2-methylallyloxy)benzene

To a solution of 5-(benzyloxy)-2-bromophenol (Simas, A. B. C., et al,Synthesis, (1999):1017-21) (8.15 g, 29.3 mmol) in DMF (150 mL) was addedpotassium carbonate (4.46 g, 32.2 mmol) slowly at 0° C. The mixture wasstirred at ambient temperature for half an hour, followed by theaddition of 3-bromo-2-methylpropene (3.35 mL, 32.2 mmol) during half anhour at 0° C. The mixture was stirred at ambient temperature overnightand quenched with saturated ammonium chloride (50 mL). The aqueousmixture was extracted with ethyl acetate (3×200 mL). The combinedorganic layers was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/20) to give the title compound(10.0 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.29 (m, 5H), 6.53 (d,1H), 6.45 (dd, 1H), 5.15-4.94 (m, 4H), 4.43 (s, 2H), 1.82 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 159.1, 155.6, 140.1, 136.5, 133.1, 128.6, 128.1,127.5, 112.9, 107.2, 103.3, 102.0, 72.4, 70.3, 19.3.

B. Synthesis of 6-(benzyloxy)-3,3-dimethyl-2,3-dihydrobenzofuran

To a solution of 4-(benzyloxy)-1-bromo-2-(2-methylallyloxy)benzene (5.00g, 15.1 mmol) in benzene (400 mL) was added tributyltin hydride (7.42mL, 27.2 mmol) and benzoyl peroxide (0.70 g, 2.90 mmol) at 0° C. Theresulting mixture was refluxed at 100° C. overnight. After cooling downto ambient temperature, the mixture was washed with water, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatography(ethyl acetate/hexane, 1/20) to give the title compound (3.48 g, 91%):MS (ES+) m/z 255.6 (M+1).

C. Synthesis of 3,3-dimethyl-2,3-dihydro-1-benzofuran-6-ol

To a solution of 6-(benzyloxy)-3,3-dimethyl-2,3-dihydrobenzofuran (3.48g, 13.7 mmol) in methanol (200 mL) was added Pd/C (1.45 g) and themixture was hydrogenated under 40 psi of hydrogen overnight. Thereaction mixture was filtered through celite, washed with methanol. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto column chromatography (ethyl acetate/hexane, 1/7) to give the titlecompound (1.66 g, 74%): MS (ES+) m/z 165.4 (M+1).

Preparation 26 Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace 1,3-benzodioxol-5-ol with2,3-dihydrobenzofuran-5-ol, (Alabaster, R. J., et al.; Synthesis (1988),12:950-2) and 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-(diphenylmethyl)-1H-indole-2,3-dione, the title compound was obtained:MS (ES+) m/z 472.2 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 434.4 (M+1).

C. Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

To a solution of1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one(1.01 g, 2.30 mmol) in THF (50.0 mL) was added paraformaldehyde (1.00 g,30.0 mmol). Argon was bubbled through the reaction mixture for one hourfollowed by the addition of diisopropylamine (1.00 g, 10.0 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 20 hoursand diluted with ethyl acetate (100 mL). The resulting mixture waswashed with water (2×50.0 mL), dried over sodium sulfate and filtered.The filtrate was concentrated in vacuo to dryness to give 0.67 g (65%)of the title compound: MS (ES+) m/z 486.4 (M+23).

Preparation 27 Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1.3-dihydro-2H-indol-2-oneA. Synthesis of ethyl2-(2-(tert-butoxycarbonylamino)-6-methoxyphenyl)-2-oxoacetate

To a solution of tert-butyl 3-methoxyphenylcarbamate (25.6 g, 0.11 mol)in THF (300 mL) was added n-BuLi (0.25 mol, 1.6 M solution in pentane)at −78° C. The resulted solution was stirred at 0° C. for 3 hours andre-cooled to −78° C. followed by the addition of diethyl oxalate (20.1g, 0.14 mol). The mixture was stirred at −78° C. for 45 min and atambient temperature for one hour, and quenched with 1 N HCl. The mixturewas extracted with ether. The organic solution was dried over sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to column chromatography to give 3.70 g (27%based on recovered starting material) of the title compound: MS (ES+)m/z 324.3 (M+1).

B. Synthesis of 4-methoxy-1H-indole-2,3-dione

A mixture of ethyl2-(2-(tert-butoxycarbonylamino)-6-methoxyphenyl)-2-oxoacetate (3.70 g,110 mmol) and 10% H₂SO₄ (100 mL) was heated at 100° C. for 10 hours.After cooling down to ambient temperature, the reaction mixture wasextracted with ether (3×100 mL). The combined ether solution was washedwith water (2×50.0 mL), dried over sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto column chromatography to give 0.37 g (19%) of the title compound: MS(ES+) m/z 200.1 (M+23).

C. Synthesis of4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 1A, and makingnon-critical variations to replace 4-bromoindole with4-methoxy-1H-indole-2,3-dione, and 1-bromopentane with2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (26%): MS (ES+) m/z 348.2 (M+23).

D. Synthesis of3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furil]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-indole-2,3-dione,the title compound was obtained (56%): MS (ES+) m/z 486.4 (M+23).

E. Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furil]methyl}-1,3-dihydro-2H-indol-2-one,the title compound was obtained (86%): MS (ES+) m/z 448.4 (M+1).

F. Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1.3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 26C, and makingnon-critical variations to replace1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-onewith3-(6-hydroxy-1,3-benzodioxol-5-yl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one,the title compound was obtained (64%): MS (ES+) m/z 500.4 (M+23).

Preparation 28 Synthesis of4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of 4,7-dichloro-1-pentyl-1H-indole-2,3-dione

To a mixture of sodium hydride (0.17 g, 6.94 mmol, 60% dispersion inmineral oil) in anhydrous N,N-dimethylformamide (5.00 mL) was added asolution of 4,7-dichloro-1H-indole-2,3-dione (1.00 g, 4.60 mmol) inN,N-dimethylformamide (5.00 mL) at 0° C. The brown reaction mixture wasstirred for 0.5 h followed by the addition of a solution of1-bromopentane (0.84 g, 5.55 mmol) in anhydrous N,N-dimethylformamide(5.00 mL). The reaction mixture was stirred at ambient temperature for16 h and poured into wet ethyl ether (30.0 mL). After the organic layerwas separated, it was washed with water (2×20.0 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The gummy residue was dried under vacuum and the solidwas triturated with ether to give the title compound (0.98 g, 98%): MS(ES+) m/z 286.2 (M+1).

B. Synthesis of4,7-dichloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with4,7-dichloro-1-pentyl-1H-indole-2,3-dione, the title compound wasobtained (68%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.61 (s, br,1H), 7.26 (t, 1H), 7.03 (d, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.86 (dd,2H), 4.21 (s, br, 1H), 4.01-3.96 (m, 2H), 1.73-1.58 (m, 2H), 1.34-1.21(m, 4H), 0.84 (t, 3H); MS (ES+) m/z 408.2 (M−17).

C. Synthesis of4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith4,7-dichloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (72%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.27-7.23 (m, 1H), 7.03 (d, 1H), 6.55 (s, 1H), 6.04 (s, 1H),5.84 (dd, 2H), 5.03 (s, 1H), 4.09-3.99 (m, 2H), 1.72-1.62 (m, 2H),1.33-1.24 (m, 4H), 0.86 (t, 3H); MS (ES+) m/z 409.2 (M+1).

D. Synthesis of4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (94%) as a gummy solid: MS (ES+) m/z439.3 (M+1).

Preparation 29 Synthesis of ethyl2-(4-chloro-3-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-2-oxoindolin-1-yl)acetateA. Synthesis of ethyl(4-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace isatin with4-chloro-1H-indole-2,3-dione, and (2-bromoethyl)cyclopropane with ethylbromoacetate, the title compound was obtained (95%) as a colorlesssolid: ¹H NMR (300 MHz, CDCl₃) δ 7.48 (t, 1H), 7.08 (d, 1H), 6.67 (d,1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 268.6 (M+1).

B. Synthesis of ethyl[4-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, the titlecompound was obtained (75%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ8.70 (br, 1H), 7.31 (t, 1H), 7.12 (d, 1H), 6.68 (d, 1H), 6.46 (d, 2H),4.53-4.46 (m, 2H), 4.18 (q, 2H), 3.08-2.88 (m, 2H), 1.23 (t, 3H); MS(ES+) m/z 387.8 (M−17).

C. Synthesis ethyl[4-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith ethyl[4-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (75%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.33-7.27 (m, 2H), 7.12 (d, 1H), 6.71 (d, 1H), 6.50-6.48 (m,1H), 5.10 (s, 1H), 4.54-4.42 (m, 4H), 4.19 (q, 2H), 3.11-2.90 (m, 2H),1.23 (t, 3H); MS (ES+) m/z 388.8 (M+1).

D. Synthesis of ethyl[4-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[4-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (99%) as a gummy solid: MS (ES+) m/z418.7 (M+1).

Preparation 30 Synthesis of3-hydroxy-3-[6-(hydroxymethyl)-1,3-benzodioxol-5-yl]-1-pentyl-1,3-dihydro-2H-indol-2-one

To a solution of (6-bromo-1,3-benzodioxol-5-yl)methanol (Mann, J., etal, J. Chem. Soc. Perkin Trans. 1 (1984):2081-8) (1.27 g, 5.50 mmol) inTHF (45.0 mL) was added n-BuLi (5.00 mL, 2.0 M, 10.0 mmol) dropwise at−75° C. The reaction mixture was stirred at −75° C. for 45 min followedby the addition of a solution of 1-pentyl-1H-indole-2,3-dione (1.00 g,4.60 mmol) in THF (20.0 mL) at −75° C. The resulting mixture was stirredat ambient temperature for 12 hrs and quenched with ammonium chloridesolution (5.00 mL). More ethyl acetate and water were added andseparated. The organic layer was concentrated in vacuo to dryness. Theresidue was subjected to column chromatography eluting with 50%EtOAc:Hexanes to yield the title compound (0.29 g, 25%) as a solid: ¹HNMR (300 MHz, CDCl₃) δ 7.38-7.24 (m, 2H), 7.11 (t, 1H), 6.91 (d, 1H),6.81(s, 1H), 6.43 (s, 1H), 5.90-5.87 (m, 2H), 4.77 (dd, 2H), 3.75-3.56(m, 2H), 1.75-1.58 (m, 2H), 1.26-1.35 (m, 2H), 0.89-0.83 (m, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 177.8, 147.4, 147.2, 142.8, 133.5, 132.2, 131.1,130.1, 125.3, 123.8, 111.4, 109.2, 108.1, 101.5, 79.5, 64.7, 40.4, 29.0,26.8, 22.3, 13.9; MS (ES+) m/z 352.1 (M−17).

Preparation 31 Synthesis of ethyl[1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetateA. Synthesis of 1-hexyl-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane withn-bromohexane, the title compound was obtained (90%) as a viscous gum:¹H NMR (300 MHz, CDCl₃) δ 7.58-7.51 (m, 2H), 7.08 (t, 1H), 6.87 (d, 1H),3.68 (t, 2H), 1.71-1.62 (m, 2H), 1.41-1.22 (m, 6H), 0.85 (t, 3H).

B. Synthesis of1-hexyl-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-hexyl-1H-indole-2,3-dione, the title compound was obtained (53%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.44 (br, 1H), 7.47-7.44 (m,1H), 7.40-7.34 (m, 1H), 7.17 (t, 1H), 6.89 (d, 1H), 6.55 (s, 1H), 6.21(s, 1H), 5.84-5.82 (m, 2H), 4.58 (br, 1H), 3.71-3.56 (m, 2H), 1.67-1.62(m, 2H), 1.32-1.21 (m, 6H), 0.84-0.80 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ179.0, 152.3, 148.8, 142.5, 141.3, 130.3, 129.2, 126.1, 123.7, 117.2,109.5, 106.8, 101.9, 101.4, 79.2, 40.4, 31.3, 27.1, 26.4, 22.4, 13.9; MS(ES+) m/z 352.5 (M−17).

C. Synthesis of1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith1-hexyl-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (98%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.38-7.13 (m, 3H), 6.94 (d, 1H), 6.60 (s, 1H), 6.32 (s, 1H),5.84 (dd, 2H), 5.02 (s, 1H), 3.74-3.63 (m, 2H), 1.70-1.61 (m, 2H),1.37-1.19 (m, 6H), 0.83 (t, 3H); MS (ES+) m/z 354.2 (M+1).

D. Synthesis of ethyl[1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate

To a solution of diisopropylamine (1.14 g, 11.0 mmol) in THF (10.0 mL)was added n-butyl lithium (7.00 mL, 11.0 mmol, 1.6 M solution in hexane)at −75° C. The resulting mixture was stirred at −75° C. for half an hourand added slowly to a solution of1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one inTHF (20.0 mL) at −75° C. After stirring at −75° C. for another half anhour, ethyl bromoacetate was added. The mixture was stirred at ambienttemperature for 18 hrs and quenched with saturated ammonium chloridesolution. The organic solvent was removed in vacuo and the aqueousresidue was diluted with ethyl acetate (100 mL). The organic layer waswashed with saturated ammonium chloride (25.0 mL), brine (50.0 mL),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography eluting with 40% EtOAc/Hexanes to yield the titlecompound (0.19 g, 8%) as an oil: MS (ES+) m/z 440.5 (M+1).

Preparation 32 Synthesis of4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 4-bromoisatin, the titlecompound was obtained (95%) as a beige solid: ¹H NMR (300 MHz, DMSO-d₆)δ 10.40 (s, 1H), 9.09 (s, 1H), 7.22 (s, 1H), 7.04 (t, 1H), 6.90 (d, 1H),6.75 (d, 1H), 6.43 (br, 1H), 6.21 (s, 1H), 5.88 (d, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ 178.0, 148.7, 147.0, 145.8, 139.5, 131.3, 130.8, 125.4,118.8, 118.4, 109.4, 108.9, 101.0, 97.4, 76.6; MS (ES+) m/z 366.4 (M+1),364.5 (M+1).

B. Synthesis of4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith4-bromo-3hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (95%) as a cream solid: MS (ES+) m/z348.5 (M+1), 346.3 (M+1).

C. Synthesis of4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 31D, and makingnon-critical variations to replace1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,and ethyl bromoacetate with para-formaldehyde, the title compound wasobtained (70%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.00(br, 1H), 7.13-6.95 (m, 3H), 6.84 (d, 1H), 6.16 (d, 1H), 5.90-5.84 (m,2H), 5.16-4.83 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.8, 150.4, 147.1,146.8, 139.8, 130.2, 129.3, 125.8, 117.7, 115.8, 109.3, 107.9, 101.2,97.6, 63.5, 57.4.

Preparation 33 Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 4-bromoisatin, and1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compoundwas obtained (78%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.36 (s, 1H), 9.15 (s, 1H), 7.49 (1H), 7.04 (t, 1H), 6.89 (d, 1H), 6.74(d, 1H), 6.35 (br, 1H), 5.90 (s, 1H), 4.45 (t, 2H), 3.05 (t, 2H); ¹³CNMR (75 MHz, DMSO-d₆) δ 178.4, 160.2, 154.0, 145.7, 131.6, 130.7, 125.5,125.4, 118.9, 117.7, 116.1, 108.8, 96.8, 76.9, 71.8, 29.1; MS (ES−) m/z344.4 (M−17), 360.4 (M−1).

B. Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (62%) as a solid: MS (ES+) m/z 346.5(M+1), 348.5 (M+1).

C. Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 31D, and makingnon-critical variations to replace1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,and ethyl bromoacetate with para-formaldehyde, the title compound wasobtained that was used directly for further reaction.

Preparation 34 Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 4-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione

To a solution of 4-bromoisatin (8.94 g, 39.5 mmol) in anhydrousN,N-dimethylformamide (100 mL) was added sodium hydride (3.34 g, 86.9mmol, 60% dispersion in mineral oil) in portions at 0° C. The brownreaction mixture was stirred for 30 min followed by the addition of asolution of 2-(bromomethyl)pyridine hydrobromide (10.0 g, 39.5 mmol)neutralized with sodium hydride (1.52 g, 39.5 mmol, 60% dispersion inmineral oil) in N,N-dimethylformamide at 0° C. The reaction mixture wasstirred for 16 h and quenched with water (100 mL). The reaction mixturewas extracted with diethyl ether (3×100 mL) and the aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic layers waswashed with water (5×200 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas triturated with ether to afford the title compound (10.6 g, 85%) asa brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, 1H), 7.67 (t, 1H),7.30 (t, 2H), 7.25-7.19 (m, 2H), 6.94 (d, 1H), 5.04 (s, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ 180.5, 157.3, 154.2, 152.3, 149.5, 138.4, 137.5, 128.6,123.3, 122.3, 121.5, 116.4, 110.3, 45.8.

B. Synthesis of4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with4-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione, and1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compoundwas obtained (91%) as a colorless solid: mp>225° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 9.29 (s, 1H), 8.54 (d, 1H), 7.70 (dt, 1H), 7.61 (br, 1H),7.32-7.26 (m, 2H), 7.07 (d, 1H), 7.00 (d, 1H), 6.72 (d, 1H), 6.60 (br,1H), 6.02 (s, 1H), 4.91 (ABq, 2H), 4.47 (t, 2H), 3.06 (d, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ 176.9, 160.4, 156.3, 153.8, 149.6, 146.1, 137.5,130.9, 130.8, 126.5, 125.8, 123.1, 121.5, 118.8, 117.3, 116.4, 108.3,96.7, 76.6, 71.9, 45.7, 29.1; MS (ES+) m/z 455.4 (M+1), 437.4 (M−17).

C. Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one

To a solution of4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one(1.12 g, 2.48 mmol) in anhydrous dichloromethane (25.0 mL) was addedtriethylamine (1.40 mL, 9.91 mmol) and SOCl₂ (0.40 mL, 4.96 mmol) at 0°C. The reaction mixture was stirred at 0° C. for 2 h and quenched withwater (30.0 mL). The organic layer was separated, washed with water(3×30.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness to give a gummy material.The residue was dissolved in acetic acid/tetrahydrofuran (3.00 mL/22.0mL) followed by the addition of zinc dust (0.81 g, 12.4 mmol) in oneportion. The reaction mixture was stirred at ambient temperature for 16h. After the solid was filtered, the solvent was removed in vacuo. Theresidue was dissolved in ethyl acetate (100 mL), washed with water(3×30.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness to give the title compound(1.50 g, 77%) as a gummy material: MS (ES+) m/z 437.3 (M+1).

D. Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (34%): MS (ES+) m/z 468.4 (M+1).

Preparation 35 Synthesis of5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-oneA. Synthesis of5-fluoro-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace isatin with 5-fluoroisatin, and(2-bromoethyl)cyclopropane with2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (59%) as a red solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.54-7.50 (m,1H), 7.47-7.44 (m, 1H), 7.20 (dd, 1H), 7.14-7.13 (m, 1H), 6.75 (d, 1H),4.99 (s, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 182.4 (d), 160.7, 158.5 (d),157.5, 153.0 (d), 146.5 (d), 139.9 (q), 124.3, 119.3 (d), 114.5 (d),112.7 (d), 112.0 (d), 110.5, 36.8.

B. Synthesis of5-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with5-fluoro-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-indole-2,3-dione,the title compound was obtained (66%) as a pale yellow solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 7.21 (s, 1H), 7.15 (dd, 1H),7.08-6.95 (m, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.22 (d, 1H), 5.90 (d,2H), 4.96 (s, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.7, 160.57, 157.4,154.0, 148.6, 147.4, 140.1 (m), 139.6 (m), 134.7 (d, ²J_(CF)=29.4 Hz),121.3, 119.5, 117.7, 115.1 (d, ¹J_(CF)=92.1 Hz), 114.5, 111.8 (d,¹J_(CF)=97.5 Hz), 109.7, 109.6, 107.2, 101.3, 97.8, 75.1, 36.9; MS (ES+)m/z 450.3 (M+1)

C. Synthesis of5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith5-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one,the title compound was obtained (72%) as a pale yellow solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 7.13 (dd, 1H), 7.02 (dd, 2H), 6.82(d, 1H), 6.59 (d, 2H), 6.39 (s, 1H), 5.87 (d, 2H), 5.07-4.96 (m, 2H),4.84 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.1, 160.5, 157.4, 153.9,150.5, 147.5, 140.2, 139.6, 139.1, 132.3 (d, ²J_(CF)=33.3 Hz), 115.3,114.5 (m), 114.2, 113.9, 111.9 (d, ¹J_(CF)=98.7 Hz), 109.9, 109.7 (d,²J_(CF)=32.7 Hz), 101.3, 98.3, 48.5, 36.8; MS (ES+) m/z 436.2 (M+1).

D. Synthesis of5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

A mixture of5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one(3.64 g, 8.41 mmol), para-formaldehyde (2.52 g, 84.1 mmol) and lithiumhydroxide monohydrate (1.06 g, 25.2 mmol) in tetrahydrofuran (84.0 mL)and water (10.0 mL) was stirred at 0° C. for 4 h. After the solvent wasremoved in vacuo, the residue was dissolved in ethyl acetate (100 mL),washed with 10% aqueous HCl (3×25.0 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to column chromatography eluting with ethylacetate/hexanes (50%) to give the title compound (0.65 g, 59%) as acolorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.11 (s, 1H), 7.12 (d, 1H),6.99-6.87 (m, 3H), 6.80 (dd, 1H), 6.48 (d, 1H), 6.23 (s, 1H), 5.89 (d,2H), 5.09 (br, 1H), 4.97 (ABq, 2H), 4.01(ABq, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.1, 160.5; MS (ES+) m/z 466.2 (M+1), 448.2 (M−17).

Preparation 36 Synthesis oftert-butyl-(2-chloromethyl-5-trifluoromethylthiophen-3-yloxy)dimethylsilaneA. Synthesis of methyl 3-tert-butyldimethylsilanyloxy-5-trifluoromethyl-2-thiophenecarboxylate

To a solution of methyl3-hydroxy-5-trifluoromethyl-2-thiophenecarboxylate (Karp, G. M., et al,Synthesis (2000), 8:1078-1080) (19.4 g, 85.8 mmol) inN,N-dimethylformamide (50.0 mL) was added imidazole (8.77 g, 129 mmol)followed by tert-butyl dimethylsilyl chloride (19.4 g, 129 mmol) at 0°C. The reaction mixture was stirred at ambient temperature overnight.More imidazole (7.50 g) and tert-butyl dimethylsilyl chloride (10.5 g)were added. The reaction mixture was stirred for another 4 h andquenched with water (100 mL). The reaction mixture was extracted withether (3×500 mL). The combined organic layers was washed with water(3×500 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto column chromatography eluting with ethyl acetate/hexanes (1/9) togive the title compound (26.5 g, 90%) as a yellow oil: ¹H NMR (300 MHz,CDCl₃) δ 6.91 (s, 1H), 3.82 (s, 3H), 0.21 (s, 6H), 0.06 (s, 9H); ¹³C NMR(75 MHz, CDCl₃) δ 161.5, 155.5, 133.7, 133.2, 123.6 (q, ¹J_(CF)=14.4Hz), 119.8, 51.9, 25.4, 18.2, −4.6.

B. Synthesis of[3-(tert-butyldimethylsilanyloxy)-5-trifluoromethylthiophen-2-yl]methanol

To a mixture of lithium aluminum hydride (1.67 g, 43.9 mmol) inanhydrous ether (75.0 mL) was added a solution of methyl 3-tert-butyldimethylsilanyloxy-5-trifluoromethyl-2-thiophenecarboxylate (10.0 g,29.3 mmol) in anhydrous ether (25.0 mL) at 0° C. The reaction mixturewas stirred at 0° C. for 30 min and quenched by the slow addition ofwater (50.0 mL). After the aqueous layer was separated, the organiclayer was washed with saturated ammonium chloride (3×20.0 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography eluting with ethyl acetate/hexanes (1/9) to give thetitle compound (6.95 g, 76%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ6.89 (s, 1H), 4.68 (s, 2H), 2.11 (br, 1H), 0.96 (s, 9H), 0.88 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ 148.0, 127.0, 124.0, 122.4 (q, ¹J_(CF)=14.7Hz), 120.5, 56.1, 25.5, 18.1, −4.6.

C. Synthesis oftert-butyl-(2-chloromethyl-5-trifluoromethylthiophen-3-yloxy)dimethylsilane

To a solution of[3-(tert-butyldimethylsilanyloxy)-5-trifluoromethylthiophen-2-yl]methanolin anhydrous dichloromethane (100 mL) was added triethylamine (4.05 g,40.0 mmol) followed by thionyl chloride (2.38 g, 20.0 mmol) at 0° C. Thereaction mixture was stirred for 30 min and quenched with water (50.0mL). After separation, the organic layer was washed with water (3×50.0mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography eluting with hexane to afford the title compound (2.31 g,70%) as a yellow oil, which was directly used.

Preparation 37 Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-5-methyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-5-methyl-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace isatin with 5-methylisatin, and(2-bromoethyl)cyclopropane with 1,1′-(bromomethylene)dibenzene, thetitle compound was obtained (74%) as a bright orange solid: ¹H NMR (300MHz, CDCl₃) δ 7.42-7.26 (m, 11H), 7.09 (d, 1H), 6.95 (s, 1H), 6.37 (d,1H), 2.24 (s, 3H).

B. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-(diphenylmethyl)-5-methyl-1H-indole-2,3-dione, the title compound wasobtained (92%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.23 (br,1H), 7.40-7.15 (m, 11H), 6.90-6.85 (m, 2H), 6.57 (s, 1H), 6.33 (d, 1H),6.31 (s, 1H), 5.87 (s, 2H), 4.46 (br s, 1H), 2.28 (s, 3H); MS (ES+) m/z448.4 (M−17).

C. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (84%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ 7.37-7.25 (m, 9H), 7.22-7.17 (m, 2H), 7.10 (s, 1H), 6.91(s, 1H), 6.86 (d, 1H), 6.63 (s, 1H), 6.40 (s, 1H), 6.38 (d, 1H), 5.88(ABq, 2H), 5.07 (s, 1H), 2.23 (s, 3H); MS (ES+) m/z 450.3 (M+1).

D. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-5-methyl-1,3-dihydro-2H-indol-2-one

To a solution of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one(1.61 g, 3.60 mmol) and para-formaldehyde (0.43 g, 14.6 mmol) indichloromethane (60.0 mL) was added diisopropylamine (7.20 mmol). Afterstirring at ambient temperature for 3 h, the reaction was quenched withsaturated aqueous ammonium chloride (60.0 mL). The organic layer wasseparated and washed with water (3×100 mL), dried over sodium sulfateand filtered. The filtrate was concentrated in vacuo to dryness. Theresidue was subjected to column chromatography eluting with ethylacetate/hexanes (20-60%) to afford the title compound (1.07 g, 63%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 10.09 (br, 1H), 7.37-7.16 (m,12H), 6.99 (s, 1H), 6.87 (d, 1H), 6.62 (s, 1H) 6.54 (s, 1H), 6.37 (d,1H), 5.87 (d, 2H), 4.45 (ABq, 2H), 2.33 (s, 3H); MS (ES+) m/z 480.4(M+1).

Preparation 38 Synthesis of3-(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with2-methyl-1,3-benzothiazol-5-ol, the title compound was obtained (81%) asa colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.90 (br, 1H), 9.05 (br,1H), 7.78 (d, 1H), 7.25 (dd, 1H), 7.10-6.95 (m, 2H), 6.90-6.80 (m, 2H),3.81-3.58 (m, 2H), 2.75 (br, 3H), 1.80-1.60 (m, 2H), 1.50-1.31 (m, 4H),0.90 (t, 3H); MS (ES+) m/z 383.4 (M+1).

B. Synthesis of3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

A suspension of3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one(0.50 g, 1.31 mmol) in hydroiodic acid (10.0 mL) was refluxed for 1.5days. The reaction mixture was concentrated in vacuo to dryness. Theresidue was used directly in next step.

C. Synthesis of3-(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 367.5 (M+1).

Preparation 39 Synthesis of (5-chloro-1,3,4-thiadiazol-2-yl)methanol

To a solution of ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (0.51 g,2.60 mmol) in anhydrous methanol (5.00 mL) was added sodium borohydride(0.30 g, 7.99 mmol) at 0° C. The reaction mixture was stirred at ambienttemperature for 16 h, diluted with acetic acid (3.00 mL) and extractedwith ethyl acetate (2×150 mL). The combined organics was washed withaqueous saturated sodium bicarbonate (3×25.0 mL) and aqueous saturatedsodium chloride (2×25.0 mL). The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo todryness to give the title compound (0.30 g, 75%) as a light yellowsemi-solid: ¹H NMR (300 MHz, CDCl₃) δ 5.04 (s, 2H), 2.80 (br, 1H); MS(ES+) 151.1 (M+1), 153.1 (M+1).

Preparation 40 Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with3,3-dimethyl-2,3-dihydro-1-benzofuran-6-ol, the title compound wasobtained: MS (ES+) m/z 478.5 (M+1).

B. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (73% for two steps): ¹H NMR (300 MHz,CDCl₃) δ 7.38-7.20 (m, 12H), 7.11-7.04 (m, 2H), 6.97 (s, 1H), 6.58 (s,1H), 6.57-6.51 (m, 1H), 6.50 (s, 1H), 5.08 (s, 1H), 4.19 (s, 2H), 1.25(s, 3H), 1.18 (s, 3H); MS (ES+) m/z 426.6 (M+1).

C. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 26C, and makingnon-critical variations to replace1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 492.5 (M+1)

Preparation 41 Synthesis of7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of7-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with7-fluoro-1H-indole-2,3-dione, the title compound was obtained (80%): ¹HNMR (300 MHz, DMSO-d₆) δ 10.66 (s, 1H), 9.11 (s, 1H), 7.18 (s, 1H),7.07-6.98 (m, 1H), 6.83-6.74 (m, 1H), 6.66 (d, 1H), 6.48 (s, 1H), 6.18(s, 1H), 5.92-5.85 (m, 2H); MS (ES+) m/z 304.5 (M+1).

B. Synthesis of7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith7-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (100%): ¹H NMR (300 MHz, DMSO-d₆) δ10.84 (s, 1H), 9.22 (s, 1H), 7.01 (t, 1H), 6.87-6.78 (m, 1H), 6.71 (d,1H), 6.62 (s, 1H), 6.35 (s, 1H), 5.90-5.85 (m, 2H), 4.67 (s, 1H); MS(ES+) m/z 288.5 (M+1).

Preparation 42 Synthesis of ethyl[4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of ethyl[4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compoundwas obtained (68%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.66 (br,1H), 7.31-7.19 (m, 3H), 6.73 (dd, 1H), 6.49-6.45 (m, 1H), 5.09-4.36 (m,4H), 4.20 (q, 2H), 3.14-2.90 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 432.2(M−17).

B. Synthesis of ethyl[4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith ethyl[4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (81%) as a white solid: ¹H NMR(CDCl_(3,) 300 MHz) δ 7.31-7.19 (m, 3H), 6.75 (d, 1H), 6.50-6.45 (m,1H), 5.08 (s, 1H), 5.09-4.36 (m, 4H), 4.20 (q, 2H), 3.14-2.90 (m, 2H),1.23 (t, 3H); MS (ES+) m/z 433.3 (M+1).

C. Synthesis of ethyl[4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (99%): MS (ES+) m/z 463.2 (M+1).

Preparation 43 Synthesis of ethyl[5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of ethyl(5-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace isatin with5-chloro-1H-indole-2,3-dione, and (2-bromoethyl)cyclopropane with ethyl2-bromoacetate, the title compound was obtained (98%) as solid: ¹H NMR(300 MHz, CDCl₃) δ 7.60 (d, 1H), 7.54 (dd, 1H), 6.74 (d, 1H), 4.46 (s,2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 268.6 (M+1).

B. Synthesis of ethyl[5-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith ethyl (5-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compoundwas obtained (85%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (br,1H), 7.31-7.24 (m, 2H), 6.92 (d, 1H), 6.68 (s, 1H), 6.46 (s, 1H),4.53-4.46 (m, 2H), 5.09-4.40 (d, 2H), 4.18 (q, 2H), 3.08-2.88 (m, 2H),1.23 (t, 3H); MS (ES+) m/z 387.8 (M−17).

C. Synthesis of ethyl[5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[5-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (94%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.30-7.24 (m, 2H), 6.72 (d, 1H), 6.66 (s, 1H), 6.39 (s, 1H),5.05 (s, 1H), 4.53-4.46 (m, 4H), 4.21 (q, 2H), 3.14-2.94 (m, 2H), 1.25(t, 3H); MS (ES+) m/z 388.8 (M+1).

D. Synthesis of ethyl[5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith ethyl[5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (99%): MS (ES+) m/z 418.7 (M+1).

Preparation 44 Synthesis of methyl[3-(4-chloro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of methyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane withmethyl bromoacetate, the title compound was obtained (72%): ¹H NMR (300MHz, CDCl₃) δ 7.64-7.53 (m, 2H), 7.14 (t, 1H), 6.77 (d, 1H), 4.48 (s,2H), 3.76 (s, 3H); MS (ES+) m/z 220.4 (M+1).

B. Synthesis of methyl[3-(4-chloro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith methyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and1,3-benzodioxol-5-ol with 3-chlorophenol, the title compound wasobtained (29%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.10 (s,1H), 7.48 (d, 1H), 7.38 (t, 1H), 7.19 (t, 1H), 7.01 (br, 1H), 6.80-6.64(m, 3H), 5.28 (br s, 1H), 4.51 (d, 1H), 4.44 (d, 1H), 3.75 (s, 3H); MS(ES+) m/z 370.5 (M+23), 372.4 (M+23).

C. Synthesis of methyl[3-(4-chloro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith methyl[3-(4-chloro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (83%) as a semi-solid; ¹H NMR (300 MHz,CDCl₃) δ 7.36 (t, 1H), 7.29 (bd, 1H), 7.18 (t, 1H), 6.95 (br, 1H),6.86-6.78 (m, 3H), 5.13 (br, 1H), 4.55 (d, 1H), 4.45 (d, 1H), 3.75 (s,3H); MS (ES+) m/z 332.5 (M+1), 334.5 (M+1).

D. Synthesis of methyl[3-(4-chloro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith methyl[3-(4-chloro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained: MS (ES+) m/z 362.5 (M+1) 364.5 (M+1).

Preparation 45 Synthesis of ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateA. Synthesis of ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2B, and non-criticalvariations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione withethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, the title compoundwas obtained as a brown oil: MS (ES+) m/z 364.3 (M+1), 348.5 (M−17).

B. Synthesis of ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (83%) as a light yellow oil: ¹H NMR (300MHz, CDCl₃) δ 7.39 (t, 1H), 7.34 (d, 1H), 7.26-7.22 (m, 1H), 6.92-6.82(m, 2H), 6.73 (dd, 1H), 5.11 (br, 1H), 4.50 (d, 1H), 4.43 (d, 1H), 4.21(q, 2H), 1.23 (t, 3H); MS (ES+) m/z 448.5 (M+1).

C. Synthesis of ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith methyl[3-(4-chloro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained: MS (ES+) m/z 378.3 (M+1), 361.3 (M−17).

Preparation 46 Synthesis of3-(4-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1C, and makingnon-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dionewith 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with3-bromophenol, the title compound was obtained (48%) as a white solid:¹H NMR (300 MHz, CDCl₃) δ 9.66 (br, 1H), 7.50-7.38 (m, 2H), 7.24-7.16(m, 2H), 6.98-6.86 (m, 2H), 6.64 (d, 1H), 4.15 (br, 1H), 3.80-3.55 (m,2H), 1.75-1.62 (m, 2H), 1.40-1.34 (m, 4H), 0.89 (t, 3H); MS (ES+) m/z391.4 (M+1), 393.4 (M+1).

B. Synthesis of3-(4-bromo-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (91%) as a white powder: ¹H NMR (300MHz, CDCl₃) δ 7.40 (t, 1H), 7.31 (d, 1H) 7.24-7.23 (m, 2H), 7.01-6.91(m, 2H), 6.74 (d, 1H), 5.05 (br, 1H), 3.80-3.65 (m, 2H), 1.75-1.63 (m,2H), 1.38-1.29 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 374.4 (M+1), 376.4(M+1).

C. Synthesis of3-(4-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith 3-(4-bromo-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained: R_(f)=0.5 (EtOAc/Hexanes, 1/4).

Preparation 47 Synthesis of3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with isatin,1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained(71%) as a yellowish solid: MS (ES+) m/z 319.4 (M+1), 321.4 (M+1).

B. Synthesis of 3-(5-bromo-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1D, and makingnon-critical variations to replace4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one,the title compound was obtained (98%) as a white powder: MS (ES+) m/z306.2 (M+1), 304.2 (M+1).

C. Synthesis of3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 35D, and makingnon-critical variations to replace5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-onewith 3-(5-bromo-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one, the titlecompound was obtained: MS (ES+) m/z 334.2 (M+1), 336.2 (M+1).

Preparation 48 Synthesis of1-(diphenylmethyl)-3-(hydroxymethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with3-(trifluoromethoxy)phenol, the title compound was obtained (75%): MS(ES+) m/z 514.5 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-hydroxy-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one,the title compound was obtained (82%): MS (ES+) m/z 498.4 (M+23).

C. Synthesis of1-(diphenylmethyl)-3-(hydroxymethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 488 (M−17), 528 (M+23).

Preparation 49 Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace 1,3-benzodioxol-5-ol with2,3-dihydrobenzofuran-6-ol (Foster et al., J. Chem. Soc. 1948:2254-2258)and 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-(diphenylmethyl)-1H-indole-2,3-dione, the title compound was obtained(68%) as a white solid: MS (ES+) m/z 450.4 (M+1).

B. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (67%) as a white solid: MS (ES+) m/z434.3 (M+1).

C. Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-(3-hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 26C, and makingnon-critical variations to replace1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-onewith1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (45%) as a white solid: MS (ES+) m/z464.5 (M+1).

Preparation 50 Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace 1,3-benzodioxol-5-ol with2,3-dihydrobenzofuran-6-ol and1-(2-cyclopropylethyl)-1H-indole-2,3-dione with4-bromo-1H-indole-2,3-dione, the title compound was obtained (78%) as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.15 (s, 1H),7.49 (1H), 7.04 (t, 1H), 6.89 (d, 1H), 6.74 (d, 1H), 6.35 (br, 1H), 5.90(s, 1H), 4.45 (t, 2H), 3.05 (t, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.4,160.2, 154.0, 145.7, 131.6, 130.7, 125.5, 125.4, 118.9, 117.7, 116.1,108.8, 96.8, 76.9, 71.8, 29.1; MS (ES−) m/z 344.4 (M−17), 360.4 (M−1).

B. Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith4-bromo-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (62%) as a white solid: MS (ES+) m/z346.5 (M+1), 348.5 (M+1).

C. Synthesis of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 14C, and makingnon-critical variations to replace3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one with4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (16%): R_(f)=0.21 (EtOAc/Hexanes, 7/3).

Preparation 51 Synthesis of7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-oneA. Synthesis of7-fluoro-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 1A, and makingnon-critical variations to replace 4-bromoindole with 7-fluoroisatin,and 1-bromopentane with 2-(bromomethyl)-5-(trifluoromethyl)furan, thetitle compound was obtained (34%): MS (ES+) m/z 336.2 (M+23).

B. Synthesis of7-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with7-fluoro-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1H-indole-2,3-dione,the title compound was obtained (75%): MS (ES+) m/z 474.3 (M+23).

C. Synthesis of7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith7-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one,the title compound was obtained (65%): MS (ES+) m/z 436.4 (M+1).

D. Synthesis of7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 26C, and makingnon-critical variations to replace1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-onewith7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one,the title compound was obtained (67%): MS (ES+) m/z 488.4 (M+23).

Preparation 52 Synthesis of3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with2,3-dihydrobenzofuran-6-ol, the title compound was obtained (90%) as awhite powder: MS (ES+) m/z 376.3 (M+23).

B. Synthesis of3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (76%): MS (ES+) m/z 338.3 (M+1).

C. Synthesis of3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (46%): MS (ES+) m/z 368.3 (M+1), 380.4(M+23).

Preparation 53 Synthesis of3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with4-bromophenol, the title compound was obtained (90%) as an orange solid:MS (ES+) m/z 486.2 (M+1), 488.2 (M+1).

B. Synthesis of3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 15B, and makingnon-critical variations to replace3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one,the title compound was obtained (99%) as a white powder: ¹H NMR (300MHz, CDCl₃) δ 7.39-7.20 (m, 11H), 7.11-7.06 (m, 4H), 6.82 (d, 1H),6.57-6.51 (m, 1H), 5.04 (s, 1H); MS (ES+) m/z 471.2 (M+1), 473.2 (M+1).

C. Synthesis of3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 26C, and makingnon-critical variations to replace1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-onewith3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained: MS (ES+) m/z 500.4 (M+1), 502.4 (M+1).

Preparation 54 Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-pentyl-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 2A, and makingnon-critical variations to replace (2-bromoethyl)cyclopropane with1-bromopentane, the title compound was obtained (72%) as a red solid: ¹HNMR (300 MHz, CDCl₃) δ 7.90 (d, 1H), 7.53-7.45 (m, 1H), 7.03-6.97 (m,1H), 6.82 (d, 1H), 3.64-3.57 (m, 2H), 1.68-1.52 (m, 2H), 1.34-1.21 (m,4H), 0.79 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 183.6, 158.1, 151.0, 138.4,125.3, 123.5, 117.5, 110.2, 40.2, 28.9, 26.9, 22.2, 13.9.

B. Synthesis of3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with1-pentyl-1H-indole-2,3-dione, the title compound was obtained (47%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.41 (s, 1H), 7.46 (dd, 1H),7.37 (dt, 1H), 7.16 (dt, 1H), 6.89 (d, 1H), 6.53 (s, 1H), 6.22 (s, 1H),5.83 (dd, 2H), 4.70 (br, 1H), 3.73-3.54 (m, 2H), 1.69-1.60 (m, 2H),1.34-1.26 (m, 4H), 0.85 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.9, 152.2,148.8, 142.5, 141.3, 130.3, 129.3, 126.1, 123.8, 117.1, 109.5, 106.8,101.8, 101.4, 79.3, 40.4, 28.9, 26.8, 22.3, 13.9; MS (ES+1) m/z 355.5(M+1).

C. Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2C, and makingnon-critical variations to replace1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-onewith3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (81%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ 9.67 (br, 1H), 7.39-7.29 (m, 2H), 7.18-7.13 (m, 1H), 6.94(d, 1H), 6.62 (s, 1H), 6.32 (s, 1H), 5.84 (dd, 2H), 5.01 (s, 1H),3.71-3.63 (m, 2H), 1.71-1.61 (m, 2H), 1.35-1.27 (m, 4H), 0.86 (t, 3H);¹³C NMR (75 MHz, CDCl₃) δ 178.8, 151.3, 147.6, 143.9, 141.53, 128.7,126.4, 126.2, 123.1, 115.3, 109.4, 106.5, 101.5, 101.2, 47.4, 40.5,28.9, 26.9, 22.3, 13.9; MS (ES+) m/z 340 (M+1).

D. Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1E, and makingnon-critical variations to replace4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-onewith3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (67%): ¹H NMR (300 MHz, CDCl₃) δ10.85-10.63 (br, 1H), 7.48-7.35 (m, 2H), 7.28-7.19 (m, 1H), 6.96 (d,1H), 6.52 (d, 2H), 5.82 (dd, 2H), 4.63 (d, 1H), 4.11 (d, 1H), 3.70 (d,2H), 2.04-1.74 (br, 1H), 1.65-162 (m, 2H), 1.31-1.24 (m, 4H), 0.84 (t,3H); ¹³C NMR (75 MHz, CDCl₃) δ 180.3, 152.6, 148.1, 143.2, 141.3, 129.2,129.1, 126.2, 123.3, 112.4, 109.6, 108.2, 101.9, 101.3, 64.6, 59.8,40.6, 28.9, 26.9, 22.2, 13.9; MS (ES+) m/z 370.1 (M+1).

Example 1 Synthesis of1′-(2-cyclopropylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(0.92 g, 2.51 mmol) in anhydrous THF (20.0 mL) was addedtriphenylphosphine (0.82 g, 3.13 mmol) and diethyl azodicarboxylate(0.55, 3.13 mmol) at −78° C. The brown reaction solution was stirred atambient temperature for 16 h, and quenched with saturated ammoniumchloride (50.0 mL). The organic solvent was removed under reducedpressure and the aqueous mixture was extracted with ethyl acetate(3×50.0 mL). The combined organic layers were dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo todryness. The brown residue was subjected to column chromatographyeluting with ethyl acetate/hexane (5% to 20%, gradient) to give thetitle compound (0.63 g, 72%) which was crystallized from ether to afforda colorless solid: mp 125-127° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.25(m, 1H), 7.14 (d, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.49 (s, 1H), 6.11(s, 1H), 5.84 (m, 2H), 4.76 (m, 2H), 3.93-3.74 (m, 2H), 1.65-1.57 (m,2H), 0.76-0.56 (m, 1H), 0.48-0.41 (m, 2H), 0.08-0.03 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ 177.4, 155.9, 148.8, 142.6, 142.3, 132.4, 128.8,124.0, 123.1, 119.5, 108.6, 103.1, 101.5, 93.6, 80.6, 58.2, 40.5, 32.5,30.8, 8.7, 4.4; MS (ES+) m/z 350.3 (M+1).

Example 1.1 Synthesis of1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 1, and makingnon-critical variations using3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (80%) as a white solid: mp 85-87° C.; ¹HNMR (300 MHz, CDCl₃) δ 7.28 (t, 1H), 7.15 (d, 1H), 7.02 (t, 1H), 6.89(d, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.84 (dd, 2H), 4.77 (ABq, 2H),3.85-3.62 (m, 2H), 1.76-1.66 (m, 2H), 1.40-1.33 (m, 4H), 0.89 (t, 3H);¹³C NMR (75 MHz, CDCl₃) δ 177.3, 155.9, 148.8, 142.4, 142.3, 132.5,128.9, 123.9, 119.6, 108.6, 103.0, 101.5, 93.6, 80.5, 58.2, 40.4, 29.0,27.1, 22.3, 14.0; MS (ES+) m/z 352 (M+1).

Example 1.2 Synthesis of4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained as a colorless solid: ¹H NMR (300 MHz,CDCl₃) δ 7.16 (d, 1H), 7.15 (s, 1H), 6.84 (dd, 1H), 6.45 (s, 1H), 6.06(s, 1H), 5.86 (dd, 2H), 4.90 (ABq, 2H), 3.83-3.60 (m, 2H), 1.74-1.64 (m,2H), 1.39-1.28 (m, 4H), 0.89 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.1,157.2, 149.1, 144.6, 142.0, 130.3, 130.1, 127.0, 120.0, 116.5, 107.6,102.5, 101.5, 93.3, 77.3, 59.6, 40.6, 29.0, 27.0, 22.3, 14.0; MS (ES+)m/z 430 (M+1).

Example 1.3 Synthesis of ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using ethyl[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained as a white powder in 90% yield: ¹H NMR(300 MHz, DMSO-d₆) δ 7.31-7.26 (m, 1H), 7.17-7.00 (m, 3H), 6.67 (s, 1H),6.18 (s, 1H), 5.90-5.89 (m, 2H), 4.76-4.66 (m, 2H), 4.59 (s, 2H), 4.13(q, 2H), 1.17 (t, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.3, 168.3, 155.6,148.8, 142.4, 142.1, 132.0, 129.3, 124.1, 123.7, 120.4, 109.6, 103.3,101.9, 93.8, 79.8, 61.8, 57.8, 41.8, 14.5; MS (ES+) m/z 390.2 (M+23).

Example 1.4 Synthesis of methyl2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using methyl2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoateto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained as a white powder in 74% yield: mp166-167° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.05 (m, 1H), 7.44 (m, 1H), 7.34(t, 1H), 7.22-7.10 (m, 3H), 7.03 (m, 1H), 6.70 (d, 1H), 6.52 (s, 1H),6.21 (s, 1H), 5.90-5.84 (m, 2H), 5.52-5.33 (m, 2H), 4.99 (d, 1H), 4.72(d, 1H), 3.95 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 167.5, 156.0,148.9, 142.4, 142.3, 137.4, 132.8, 132.1, 131.4, 129.0, 128.6, 127.4,126.5, 123.9, 123.6, 119.4, 109.5, 103.1, 101.5, 93.7, 80.7, 58.4, 52.3,42.4; MS (ES+) m/z 430.3 (M+1), 452.3 (M+23).

Example 1.5 Synthesis of methyl3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using methyl3-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoateto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained as a white powder in 73% yield; ¹H NMR(300 MHz, CDCl₃) δ 7.97-7.95 (m, 2H), 7.53-7.50 (m, 1H), 7.45-7.40 (m,1H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 6.73-6.71 (m, 1H), 6.52 (s,1H), 6.20 (s, 1H), 5.86 (s, 1H), 5.18 (d, 1H), 4.72 (d, 1H), 4.80 (d,1H), 4.69 (d, 1H), 3.89 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.7, 166.6,156.0, 149.0, 142.4, 141.7, 136.1, 132.2, 131.7, 130.9, 129.2, 128.1,124.0, 123.7, 119.4, 109.2, 103.1, 101.6, 93.7, 80.5, 64.3, 58.3, 52.3,43.7; MS (ES+) m/z 430 (M+1).

Example 1.6 Synthesis of methyl4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using methyl4-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoateto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained as a white powder in 87% yield: ¹H NMR(300 MHz, CDCl₃) δ 8.01 (d, 2H), 7.38 (d, 2H), 7.18 (t, 2H), 7.02 (t,1H), 6.72 (d, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.86 (m, 2H), 5.11 (d,1H), 4.96 (d, 1H), 4.86 (d, 1H), 4.69 (d, 1H), 3.89 (s, 1H); ¹³C NMR (75MHz, CDCl₃) δ 177.7, 166.6, 156.0, 149.0, 142.4, 141.8, 140.8, 132.1,130.3, 129.8, 129.0 127.3, 124.1, 123.7, 119.3, 109.2, 103.0, 102.0,93.7, 80.5, 58.3, 52.2, 43.9; MS (ES+) m/z 430.1 (M+1).

Example 1.7 Synthesis of1′-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained as a white powder in 26% yield: MS (ES+)m/z 462.3 (M+1).

Example 1.8 Synthesis ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of1′-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(2.10 g, 4.70 mmol) in EtOAc (100 mL) and acetic acid (0.10 mL) wasadded palladium on carbon (1.00 g). The reaction mixture washydrogenated under 60 psi of hydrogen at ambient temperature for 5 daysand filtered. The filtrate was concentrated in vacuo to dryness. Theresidue was subjected to column chromatography to yield the titlecompound (0.87 g, 66%) as a white powder: mp 252° C. (dec.); ¹H NMR (300MHz, CDCl₃) δ 10.55 (s, 1H), 7.25-6.84 (m, 4H), 6.64 (s, 1H), 6.22 (s,1H), 5.88 (s, 2H), 4.76-4.57 (dd, 2H); MS (ES+) m/z 282.2 (M+1).

Example 1.9 Synthesis of2-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dioneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 45% yield: ¹H NMR (300 MHz, CDCl₃) δ7.83-7.80 (m, 2H), 7.70-7.68 (m, 2H), 7.28-7.26 (m, 1H), 7.15 (d, 1H),7.05-7.00 (m, 1H), 6.86 (d, 1H), 6.48 (s, 1H), 6.23 (s, 1H), 5.85-5.83(m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.94-3.68-(m, 4H), 2.15-2.10-(m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 168.2, 155.9, 148.8, 142.4, 141.9,134.0, 132.5, 132.0, 128.9, 124.1, 123.4, 123.3, 119.4, 108.4, 103.2,101.5, 93.6, 80.4, 58.2, 38.0, 35.6, 26.8; MS (ES+) m/z 469.3 (M+1),491.3 (M+23).

Example 1.10 Synthesis of2-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]-1H-isoindole-1,3(2H)-dione

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dioneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 61% yield: ¹H NMR (300 MHz, CDCl₃) δ7.81-7.73 (m, 2H), 7.71-7.62 (m, 2H), 7.18-7.08 (m, 2H), 6.98 (t, 1H),6.87 (d, 1H), 6.43 (s, 1H), 6.29 (s, 1H), 5.91-5.81 (ABq, 2H), 4.79 (d,1H), 4.58 (d, 1H), 4.18-3.92 (m, 4H), 3.06 (t, 2H), 1.59-1.35 (br, 2H);¹³C NMR (75 MHz, CDCl₃) δ 178, 168.2, 156.1, 148.7, 142.2, 141.9, 134.1,132.4, 131.8, 128.7, 124.1, 123.4, 123.3, 119.0, 107.8, 103.7, 101.4,93.4, 80.9, 58.1, 39.0, 35.6; MS (ES+) m/z 455 (M+1), 477 (M+23).

Example 1.11 Synthesis of1′-[3-(Benzyloxy)propyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 98% yield as a pale yellow syrup: ¹HNMR (300 MHz, CDCl₃) δ 7.38-6.95 (m, 9H), 6.49 (s, 1H), 6.08 (s, 1H),5.83 (dd, 2H), 5.86 (ABq, 1H), 4.58 (ABq, 1H), 3.96-3.79 (m, 2H), 3.53(t, 2H), 2.06-2.00 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 155.9,148.8, 142.5, 142.2, 138.1, 132.3, 128.9, 127.9, 127.6, 123.9, 123.1,119.5, 108.7, 103.0, 101.4, 93.6, 80.4, 73.1, 67.4, 58.1, 37.7, 27.9; MS(ES+) m/z 430.3 (M+1).

Example 1.12 Synthesis of5,6-difluoro-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 71% yield: mp 48-50° C.; ¹H NMR (300MHz, CDCl₃) δ 7.33 (td, 1H), 7.18-7.12 (m, 2H), 6.93 (d, 1H), 6.77 (dd,1H), 6.51 (dd, 1H), 4.96 (d, 1H), 4.71 (d, 1H), 3.87-3.64 (m, 2H),1.82-1.65 (m, 2H), 1.46-1.28 (m, 4H), 0.92 (t, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 176.6, 156.8, 152.9, 149.8, 144.2, 142.6, 131.8, 129.4, 124.1,123.5, 111.7, 109.0, 100.2, 80.9, 57.9, 40.6, 29.1, 27.2, 22.5, 14.1; MS(ES+) m/z 344 (M+1).

Example 1.13 Synthesis of5-fluoro-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 3% yield: ¹H NMR (300 MHz, CDCl₃) δ7.37-7.28 (m, 1H), 7.18-7.11 (m, 1H), 7.09-7.01 (m, 1H), 6.98-6.82 (m,3H), 6.45-6.37 (m, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.63 (m, 2H),1.81-1.65 (m, 2H), 1.48-1.28 (m, 4H), 0.92 (t, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 176.7, 159.4, 156.6, 132.2, 130.1, 129.3, 124.1, 123.4, 116.3,110.8, 110.5, 108.9, 80.4, 58.4, 40.6, 29.2, 27.3, 22.5, 14.1; MS (ES+)m/z 326 (M+1).

Example 1.14 Synthesis of5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 4% yield: ¹H NMR (300 MHz, CDCl₃) δ7.38-7.23 (m, 2H), 7.17-7.01 (m, 2H), 6.93 (d, 1H), 6.84 (d, 1H), 6.79(d, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.64 (m, 2H), 1.81-1.65 (m,2H), 1.48-1.28 (m, 4H), 0.92 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.7,160.1, 142.6, 132.7, 132.1, 131.4, 129.3, 126.5, 124.1, 123.5, 113.1,112.2, 108.9, 80.3, 58.0, 40.6, 29.2, 27.3, 22.5, 14.2; MS (ES+) m/z 386(M+1), 388 (M+23).

Example 1.15 Synthesis of5-chloro-6-fluoro-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(5-chloro-4-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 80% yield; mp 74-76° C.; ¹H NMR (300MHz, CDCl₃) δ 7.38-7.27 (m, 1H), 7.18-7.02 (m, 2H), 6.94 (d, 1H), 6.77(d, 1H), 6.69 (d, 1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.87-3.64 (m, 2H),1.82-1.65 (m, 2H), 1.47-1.28 (m, 4H), 0.92 (t, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 176.5, 160.6, 157.4, 142.6, 133.9, 131.8, 129.5, 124.6, 124.1,123.5, 113.1, 109.0, 100.0, 81.2, 57.5, 40.6, 29.2, 27.2, 22.5, 14.1; MS(ES+) m/z 360 (M+1).

Example 1.16 Synthesis of6-methoxy-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(2-hydroxy-4-methoxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 99% yield: ¹H NMR (300 MHz, CDCl₃) δ7.30 (td, 1H), 7.14 (dd, 1H), 7.03 (t, 1H), 6.91 (d, 1H), 6.58 (d, 1H),6.52 (d, 1H), 6.36 (dd, 1H), 4.93 (d, 1H), 4.69 (d, 1H), 3.91-3.63 (m,2H), 3.77 (s, 3H), 1.81-1.65 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, 3H);¹³C NMR (75 MHz, CDCl₃) δ 177.4, 162.1, 161.5, 142.5, 132.9, 128.8,123.9, 123.5, 123.1, 121.0, 108.5, 107.5, 96.6, 80.5, 57.6, 55.6, 40.3,29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 338 (M+1).

Example 1.17 Synthesis of6-chloro-5-fluoro-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 44% yield: ¹H NMR (300 MHz, CDCl₃) δ7.34 (td, 1H), 7.14 (dd, 1H), 7.06 (td, 1H), 6.98 (d, 1H), 6.93 (d, 1H),6.50 (d, 1H), 4.96 (d, 1H), 4.70 (d, 1H), 3.87-3.63 (m, 2H), 1.81-1.65(m, 2H), 1.47-1.29 (m, 4H), 0.91 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ176.2, 156,9, 154.8, 151.6, 142.5, 131.5, 129.4, 128.6, 123.7, 121.7,121.9, 111.2, 108.9, 80.6, 57.9, 40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+)m/z 360 (M+1).

Example 1.18 Synthesis of1′-pentyl-5-(trifluoromethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(hydroxymethyl)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 27% yield: ¹H NMR (300 MHz, CDCl₃) δ7.48 (dd, 1H), 7.35 (td, 1H), 7.16-6.90 (m, 5H), 5.02 (d, 1H), 4.76 (d,1H), 3.91-3.65 (m, 2H), 1.82-1.67 (m, 2H), 1.47-1.29 (m, 4H), 0.91 (t,3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.5, 163.3, 142.6, 131.8, 129.8, 129.3,127.7, 124.1, 124.0, 123.9, 123.6, 121.0, 110.6, 108.9, 80.5, 57.6,40.5, 29.0, 27.1, 22.3, 13.9; MS (ES+) m/z 376 (M+1).

Example 1.19 Synthesis of5,6-dichloro-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(4,5-dichloro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 43% yield. ¹H NMR (300 MHz, CDCl₃) δ7.35 (td, 1H), 7.17-7.03 (m, 3H), 6.94 (d, 1H), 6.76 (s, 1H), 4.98 (d,1H), 4.72 (d, 1H), 3.88-3.65 (m, 2H), 1.82-1.67 (m, 2H), 1.47-1.29 (m,4H), 0.92 (t, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 176.2, 159.9, 142.5, 133.3,131.5, 129.4, 124.6, 124.5, 123.9, 123.4, 112.4, 108.9, 80.8, 57.5,40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 376 (M+1), 378 (M+1).

Example 1.20 Synthesis of1′-(diphenylmethyl)-5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained: mp 190-192° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.40-7.26 (m, 10H), 7.19-7.15 (m, 1H), 7.07-6.93 (m, 3H), 6.55-6.51(m, 1H), 6.38 (s, 1H), 6.20 (s, 1H), 4.98 (d, 1H), 4.71 (d, 1H), 4.17(s, 2H), 1.17 (s, 3H), 1.14 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.1,161.1, 161.0, 141.8, 137.9, 137.2, 132.8, 130.0, 128.6, 128.5, 128.4,128.2, 128.0, 127.8, 123.9, 123.1, 120.8, 116.1, 112.1, 93.4, 85.4,80.4, 58.7, 57.4, 41.3, 27.7, 27.6; MS (ES+) m/z 474.5 (M+1).

Example 1.21 Synthesis of5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a solution of1′-(diphenylmethyl)-5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.23 g, 0.49 mmol) in methanol (50.0 mL) was added palladium on carbon(0.10 g). The mixture was hydrogenated under 120 psi of hydrogen atambient temperature overnight. The reaction mixture was filtered throughcelite, washed with methanol. The filtrate was concentrated in vacuo todryness. The residue was subjected to column chromatography (ethylacetate/hexane, 1/2) to give the title compound (0.10 g, 68%): mp95-100° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 7.28-7.20 (m, 1H),7.15 (d, 1H), 7.03 (t, 1H), 6.95 (d, 1H), 6.43 (s, 1H), 6.40 (s, 1H),4.94 (d, 1H), 4.66 (d, 1H), 4.19 (s, 2H), 1.20 (s, 3H), 1.16 (3H); ¹³CNMR (75 MHz, CDCl₃) δ 180.4, 161.3, 161.0, 140.3, 133.0, 130.1, 128.8,124.2, 123.4, 120.0, 116.6, 110.1, 93.4, 85.5, 80.6, 58.3, 41.4, 27.7,27.6; MS (ES+) m/z 308.6 (M+1).

Example 1.22 Synthesis of4′,7′-dichloro-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one(0.69 g, 1.57 mmol) in anhydrous tetrahydrofuran (15.0 mL) was addedtriphenylphosphine (0.54 g, 2.04 mmol) followed by slow addition ofdiisopropyl azodicarboxylate (0.41 g, 2.04 mmol) at 0° C. The brownreaction mixture was stirred at ambient temperature for 16 h andquenched with ammonium chloride solution (2.00 mL). The organic solventwas removed in vacuo. The residue was dissolved in ethyl acetate (20.0mL), washed with 10% aqueous HCl solution (10.0 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatographyeluting with ethyl acetate/hexane (35%) to give a solid, which wascrystallized from ethyl acetate/ether to give the title compound (0.13g, 20%) as a colorless solid: mp 106-108° C.; ¹H NMR (300 MHz, CDCl₃) δ7.24-7.16 (m, 1H), 6.81 (d, 1H), 6.44 (s, 1H), 6.07 (s, 1H), 5.86 (dd,2H), 4.87 (dd, 2H), 4.12-4.07 (m, 2H), 1.76-1.66 (m, 2H) 1.36-1.31 (m,4H), 0.89 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 157.0, 149.2, 142.1,140.0, 132.3, 131.0, 130.2, 124.6, 116.0, 113.8, 102.3, 101.5, 93.3,77.2, 58.5, 42.1, 29.5, 28.7, 22.3, 14.0; MS (ES+) m/z 420.4 (M+1).

Example 1.23 Synthesis of4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 71% yield as a colorless solid: ¹HNMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.19-7.08 (m, 2H), 6.90 (dd,1H), 6.58 (s, 1H), 6.25 (s, 1H), 5.90 (d, 2H), 4.74 (ABq, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ 178.5, 157.0, 148.8, 144.5, 141.9, 131.2, 130.6,126.1, 119.2, 117.5, 109.8, 103.3, 101.8, 93.3, 77.6, 59.7; MS (ES−) m/z360.4 (M−1), 358.4 (M−1).

Example 1.24 Synthesis of4′-bromo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a solution of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(1.80 g, 4.80 mmol) in anhydrous ethyl acetate (50 mL) was addedtributylphosphine (1.26 g, 1.54 mL, 6.24 mmol) at 0° C. under nitrogen.A solution of di-tert-butyl azodicarboxylate (1.44 g, 6.24 mmol) inanhydrous ethyl acetate (15.0 mL) was added over 10 min. The reactionsolution was stirred for 2 h, and then quenched with saturated ammoniumchloride solution (30.0 mL). After the aqueous layer was separated, theorganic layer was washed with 10% aqueous HCl solution (2×25.0 mL),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography eluting with ethyl acetate-hexane (70%) to obtain a solidwhich was triturated with diethyl ether to give the title compound (0.64g, 37%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.77 (s, 1H),7.18-7.13 (m, 1H), 7.08 (d, 1H), 6.90 (d, 1H), 6.47 (s, 1H), 6.30 (s,1H), 4.80 (ABq, 2H), 4.46 (t, 2H), 2.92 (t, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ 178.7, 162.2, 161.7, 144.5, 131.1, 131.0, 126.1, 119.8,119.2, 119.1, 118.3, 109.7, 92.4, 77.6, 72.5, 59.2, 28.8; MS (ES−) m/z358.4 (M−1), 356.3 (M−1).

Example 1.25 Synthesis of4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one(1.81 g, 3.88 mmol), triphenylphosphine (2.04 g, 7.77 mmol) anddiisopropyl azodicarboxylate (1.57 g, 7.77 mmol) in anhydrous dioxane(60 mL) was heated at reflux for 16 h. After cooling down to ambienttemperature, the solvent was removed in vacuo. The gummy residue wasdiluted with ethyl acetate (50.0 mL), washed with water (3×25.0 mL),brine (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto column chromatography eluting with ethyl acetate/hexane (80%) to givethe title compound (0.64 g, 37%) as colorless solid: mp>200° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 8.47 (d, 1H), 7.77 (dt, 1H), 7.37 (d, 1H), 7.27(dt, 1H), 7.19-7.13 (m, 2H), 6.94 (dd, 1H), 6.61 (s, 1H), 6.33 (s, 1H),5.08 (d, 1H), 5.03 (d, 1H), 4.93 (d, 1H), 4.74 (d, 1H), 4.48 (t, J=8.6Hz, 2H), 2.96 (t, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.4, 162.2, 161.8,155.3, 149.8, 145.3, 137.6, 131.0, 130.5, 126.8, 123.3, 122.2, 119.9,119.5, 119.0, 118.1, 109.3, 92.4, 77.5, 72.5, 58.8, 45.3, 28.8; MS (ES+)m/z 451.3 (M+1).

Example 1.26 Synthesis of5′-fluoro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one(3.34 g, 7.18 mmol) in anhydrous tetrahydrofuran (80.0 mL) was addedtributylphosphine (2.18 g, 2.70 mL, 10.8 mmol) under nitrogen. Asolution of di-tert-butyl azodicarboxylate (2.49 g, 10.8 mmol) inanhydrous tetrahydrofuran (25.0 mL) was added over 10 min. The reactionsolution was stirred for 1 h, and quenched with saturated ammoniumchloride (30.0 mL). After the solvent was removed under reducedpressure, the gummy material was extracted with ethyl acetate (3×75.0mL). The organic layer was washed with 10% aqueous HCl solution (2×25.0mL), saturated aqueous sodium hydrogen carbonate (3×25.0 mL), brine(3×25.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto column chromatography eluting with ethyl acetate/hexane (30%) toafforded the title compound (1.10 g, 34%) as a colorless solid: mp139-141° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.96 (m, 1H), 6.93-6.89 (m,2H), 6.74-6.73 (m, 1H), 6.50 (s, 1H), 6.38 (d, 1H), 6.09 (s, 1H), 5.87(dd, 2H), 4.95 (ABq, 2H), 4.78 (Abq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ176.9, 161.5, 158.3, 155.9, 151.7, 149.2, 142.6, 137.1, 137.1, 133.7,118.6, 115.6, 115.3, 112.7, 112.4, 112.0, 109.7, 109.6, 109.4, 102.8,101.7, 93.8, 80.1, 58.6, 37.1; MS (ES+) m/z 448.2 (M+1).

Example 1.27 Synthesis of1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of1-(diphenylmethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-5-methyl-1,3-dihydro-2H-indol-2-one(1.31 g, 2.72 mmol) in ethyl acetate (50.0 mL) was addedtributylphosphine (0.82 g, 4.07 mmol). A solution of di-tert-butylazodicarboxylate (0.94 g, 4.07 mmol) in ethyl acetate (45.0 mL) wasadded to the above reaction mixture over a period of 5 minutes. Afterstirring for 10 minutes under N₂, the reaction was quenched withsaturated aqueous ammonium chloride (60.0 mL). The organic layer wasseparated and washed with 1.0 N hydrochloric acid solution (3×100 mL),dried over sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatographyeluting with ethyl acetate/hexane (10-50%) to afford the title compound(0.98 g, 78% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.25 (m, 10H), 7.02,(s, 1H), 6.96 (s, 1H), 6.79 (d, 1H), 6.50 (s, 1H), 6.36 (d, 1H), 6.08(s, 1H), 5.86 (d, 2H), 4.82 (ABq, 2H), 2.20 (s, 3H).

Example 1.28 Synthesis of5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A stainless steel hydrogenating vessel was successively charged with1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.90 g, 1.95 mmol), glacial acetic acid (50.0 mL) and palladiumhydroxide (0.10 g, 1.35 mmol, 20 wt % on carbon). The vessel was flushedwith nitrogen, sealed then heated to 60° C. and placed under 120 Psi ofH₂. After 4 days of stirring, the reaction mixture was diluted withethyl acetate and passed through a bed of celite. The filtrate waswashed with water (6×100 mL), dried over sodium sulfate and filtered.The filtrate was concentrated in vacuo to dryness. The residue wassubjected to column chromatography eluting with ethyl acetate/hexane(40-50%) to afford the title compound (0.25 g, 43%): mp 269-271° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 10.45 (s, 1H), 7.00 (d, 1H), 6.87 (s, 1H), 6.76(d, 1H), 6.63 (s, 1H), 6.21 (s, 1H), 5.87 (d, 2H), 4.64 (ABq, 2H), 2.17(s, 3H); MS (ES+) m/z 296.28 (M+1).

Example 1.29 Synthesis of5′-methyl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a suspension of sodium hydride (0.03 g, 0.63 mmol, 60% dispersion inmineral oil) in N,N-dimethylformamide (5.00 mL) was slowly added asolution of5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.10 g, 0.33 mmol) in N,N-dimethylformamide (5.00 mL) at 0° C. Afterstirring for 15 minutes at 0° C., a solution of2-(bromomethyl)-5-(trifluoromethyl)furan (0.11 g, 0.49 mmol) inN,N-dimethylformamide (40.0 mL) was added. The resulting mixture wasstirred at ambient temperature for 4 h and quenched with water (20.0mL). The mixture was extracted with ethyl acetate (3×25.0 mL). Thecombined organic layers was washed with water (50.0 mL) and brine(2×25.0 mL), dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was subjected to columnchromatography eluting with ethyl acetate/hexane (15-50%) to afford thetitle compound (0.11 g, 77% yield): mp 96-98° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.09 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H), 6.74 (d, 1H), 6.52(s, 1H), 6.38 (d, 1H), 6.11 (s, 1H), 5.88 (d, 2H), 4.96 (ABq, 2H), 4.80(ABq, 2H), 2.29 (s, 3H); MS (ES+) m/z 444.2 (M+1).

Example 1.30 Synthesis of6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using3-(4-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 82% yield as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 7.33 (td, 1H), 7.15-7.14 (m, 2H), 7.04 (dd, 1H),6.96-6.90 (m, 2H), 6.56 (d, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.64(m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H); ¹³C NMR (75MHz, CDCl₃) δ 176.6, 161.6, 142.5, 132.1, 129.1, 128.4, 124.4, 123.9,123.3, 122.8, 114.1, 108.8, 80.4, 57.6, 40.4, 29.0, 27.1, 22.3, 14.0; MS(ES+) m/z 386.3 (M+1), 388.3 (M+1).

Example 1.31 Synthesis of5-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 1, and makingnon-critical variations using3-(5-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (72%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.43-7.25 (m, 11H), 7.14-6.93 (m, 4H), 6.83 (d, 1H), 6.71 (d,1H), 6.52 (d, 1H), 5.0 (d, 1H), 4.73 (d, 1H); MS (ES+) m/z 484.4 (M+1),482.4 (M+1).

Example 1.32 Synthesis of2-methyl-1′-pentylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using3-(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (50%) as a white solid: mp 105-107° C.;¹H NMR (300 MHz, CDCl₃) δ 7.59 (d, 1H), 7.28 (dt, 1H), 7.02-6.92 (m,2H), 5.02 (d, 1H), 4.77 (d, 1H), 4.01 (m, 1H), 3.64 (m, 1H), 2.54 (s,3H), 1.92-1.71 (m, 2H), 1.54-1.34 (m, 4H), 0.92 (t, 3H); ¹³C NMR (75MHz, CDCl₃) δ 176.7, 169.2, 160.2, 149.2, 142.7, 138.3, 132.7, 129.0,128.6, 123.5, 122.7, 122.1, 120.2, 108.6, 108.3, 80.1, 58.1, 40.7, 29.1,27.0, 22.5, 20.2, 14.1; MS (ES+) m/z 379.5 (M+1).

Example 1.33 Synthesis of5-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using3-(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (30%) as a white solid: mp 143-145° C.;¹H NMR (300 MHz, CDCl₃) δ 7.35-7.27 (m, 2H), 7.17-6.98 (m, 3H), 6.84 (d,1H), 6.78-6.73 (m, 2H), 6.40 (d, 1H), 5.07-4.87 (m, 3H), 4.69 (d, 1H);MS (ES+) m/z 464.2 (M+1), 466.2 (M+1).

Example 1.34 Synthesis of5-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (25%) as a white solid: mp 225-228° C.;¹H NMR (300 MHz, CDCl₃) δ 10.65 (s, 1H), 7.35 (dd, 1H), 7.24 (dt, 1H),7.11 (d, 1H), 6.99-6.88 (m, 3H), 6.83 (d, 1H), 4.81 (d, 1H), 4.69 (d,1H); MS (ES+) m/z 316.1 (M+1), 318.1 (M+1).

Example 1.35 Synthesis of1-(diphenylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of1-(diphenylmethyl)-3-(hydroxymethyl)-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one(17.3 mmol) in anhydrous THF (200 mL) was added triphenylphosphine (6.34g, 24.2 mmol) followed by diethyl azodicarboxylate (4.39 mL, 24.2 mmol)at 0° C. The reaction mixture was stirred at ambient temperature for 16h, quenched with saturated ammonium chloride (40.0 mL). The aqueousmixture was extracted with ethyl acetate (3×150 mL). The combinedorganic layers was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/4) to give the title compound(6.00 g, 71%): ¹H NMR (300 MHz, CDCl₃) δ 7.45-6.51 (m, 18H), 5.08 (d,1H), 4.81 (d, 1H); MS (ES+) m/z 488 (M+1).

Example 1.36 Synthesis of6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a suspension of1′-(diphenylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(6.00 g, 12.3 mmol) in methanol (100 mL) and acetic acid (1.00 mL) wasadded 10% palladium on carbon (0.65 g, 0.62 mmol), and the mixture washydrogenated at ambient temperature under 130 psi of hydrogen for 5days. The reaction mixture was filtered over celite and the filtrate wasconcentrated in vacuo to dryness. The residue was subjected to flashchromatography eluting with 30% ethyl acetate in hexane to give thetitle compound (2.95 g, 75%) as a white solid: mp 180-182° C.; ¹H NMR(300 MHz, CDCl₃) δ 9.19 (s, 1H), 7.29-6.92 (m., 4H), 6.86-6.64 (m, 3H),5.03 (d, 1H), 4.75 (d, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 179.9, 161.9,150.6, 132.3, 129.4, 127.4, 125.6, 124.3, 124.2, 123.8, 120.5, 114.1,110.7, 104.3, 80.8, 58.2; MS (ES+) m/z 322 (M+1).

Example 1.37 Synthesis of ethyl(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using ethyl[4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained (41%) as a colorless solid: MS (ES+) m/z445.5 (M+1).

Example 1.38 Synthesis of ethyl(4′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using ethyl[4-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 63% yield as a colorless solid: MS(ES+) m/z 400.8 (M+1).

Example 1.39 Synthesis of ethyl(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using ethyl[4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 52% yield: ¹H NMR (300 MHz, CDCl₃) δ7.22-7.10 (m, 2H), 6.70 (d, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 5.0 (d,1H); 4.86 (d, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 4.28-4.18 (m, 2H), 2.79(s, 2H), 1.43 (s, 3H), 1.39 (s, 3H), 1.28 (t, 3H); MS (ES+) m/z 472.5(M+1), 474.5 (M+1).

Example 1.40 Synthesis of ethyl(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 81% yield: MS (ES+) m/z 438.4 (M+1),440.4 (M+1).

Example 1.41 Synthesis of ethyl(5′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using ethyl[5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 90% yield as a colorless solid: MS(ES+) m/z 400.8 (M+1).

Example 1.42 Synthesis of7′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A solution of7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(2.00 g, 7.00 mmol) and paraformaldehyde (2.10 g, 61.0 mmol) in THF (50mL) was degassed by bubbling through argon for one hour, followed by theslow addition of lithium diisopropylamide (48.8 mL, freshly made 0.50 Msolution, 25 mmol) at −78° C. The mixture was stirred at ambienttemperature overnight and quenched with saturated ammonium chloride(50.0 mL). The mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layers was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas dissolved in anhydrous ethyl acetate (50 mL) followed by theaddition of tributylphosphine (2.10 mL, 8.00 mmol) and di-tert-butylazodicarboxylate (1.90 g, 8.00 mmol) at 0° C. The reaction mixture wasstirred at ambient temperature for 16 h and quenched with saturatedammonium chloride (30.0 mL). The organic layer was separated, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was dissolved in methanol (70.0 mL)followed by the addition of saturated sodium bicarbonate solution (30.0mL). The resulted mixture was refluxed at 100° C. for one hour. Aftercooling down to ambient temperature, the mixture was extracted withethyl acetate (3×50.0 mL). The combined organic layers was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatography(ethyl acetate/hexane, 1/5) to give the title compound (0.27 g, 17%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.06 (s, 1H), 7.17-7.08 (m, 1H), 7.00-6.88 (m,2H), 6.64 (s, 1H), 6.33 (s, 1H), 5.92-5.85 (m, 2H), 4.74 (d, 1H), 4.62(d, 1H).

Example 1.43 Synthesis of methyl(6-chloro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using methyl[3-(4-chloro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 74% yield as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 7.29 (dt, 1H), 7.14 (dd, 1H), 7.06 (t, 1H), 6.95(d, 1H), 6.81-6.74 (m, 3H), 5.03 (d, 1H), 4.74 (d, 1H), 4.65 (d, 1H),4.44 (d, 1H), 3.75 (s, 3H); MS (ES+) m/z 344.5 (M+1), 346.5 (M+1).

Example 1.44 Synthesis of ethyl(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1.22, and makingnon-critical variations using ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one,the title compound was obtained in 46% yield as a light yellow oil: ¹HNMR (300 MHz, CDCl₃) δ 7.31 (dt, 1H), 7.16 (dd, 1H), 7.08 (dt, 1H),6.81-6.71 (m, 2H), 6.67 (dd, 1H), 4.98 (d, 1H), 4.74 (d, 1H), 4.64 (d,1H), 4.37 (d, 4.24 (q, 7.1 Hz), 1.28 (t, 3H); MS (ES+) m/z 360.5 (M+1).

Example 1.45 Synthesis of ethyl(2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)acetate

To a solution of ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate(4.20 mmol) in anhydrous THF (60.0 mL) was added triphenylphosphine(1.43 g, 5.46 mmol) and diethyl azodicarboxylate (0.95 g, 5.46 mmol) at0° C. The reaction mixture was stirred at ambient temperature for 16 hand quenched with saturated ammonium chloride (20.0 mL). The mixture wasextracted with ethyl acetate (3×50.0 mL). The combined organic layerswas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/4) to give the title compound(0.25 g, 16% in three steps): ¹H NMR (300 MHz, CDCl₃) δ 7.29 (td, 1H),7.22-7.17 (m, 1H), 7.07 (t, 1H), 6.81 (s, 1H), 6.78 (d, 1H), 6.65 (s,1H), 4.95 (d, 1H), 4.71 (d, 1H), 4.64 (d, 1H), 4.42 (d, 1H), 4.24 (q,2H), 2.84 (t, 2H), 2.73-2.65 (m, 2H), 2.10-1.95 (m, 2H), 1.29 (t, 3H);MS (ES+) m/z 364 (M+1).

Example 1.46 Synthesis of ethyl(2-oxo-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-1(2H)-yl)acetate

Following the procedure as described in EXAMPLE 1.45, and makingnon-critical variations using ethyl[3-(hydroxymethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (24% in three steps): ¹H NMR (300 MHz,CDCl₃) δ 7.29 (td, 1H), 7.19 (d, 1H), 7.07 (t, 1H), 6.79 (d, 1H), 6.66(s, 1H), 6.51 (s, 1H), 4.91 (d, 1H), 4.67 (d, 1H), 4.52 (ABq, 2H), 4.24(q, 2H), 2.77-2.51 (m, 4H), 1.77-1.64 (m, 4H), 1.29 (t, 3H); MS (ES+)m/z 378 (M+1).

Example 1.47 Synthesis of ethyl(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 1.45, and makingnon-critical variations using ethyl[4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetateto replace ethyl[3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,the title compound was obtained (41%): mp 133-134° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.26-7.15 (m, 3H), 6.78-6.58 (m, 2H), 5.08 (d, 1H), 4.91 (d,1H), 4.63 (d, 1H), 4.35 (d, 1H), 4.24 (q, 2H), 1.29 (t, 3H); ¹³C NMR (75MHz, CDCl₃) δ 176.5, 166.8, 157.1, 143.7, 130.7, 129.0, 127.8, 120.0,111.8, 111.6, 107.5, 99.8, 99.5, 62.2, 59.1, 41.7, 14.1; MS (ES+) m/z438 (M+1), 440 (M+1), 460 (M+23), 462 (M+23).

Example 1.48 Synthesis of1′-(diphenylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 1, and making non-criticalvariations using1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (43%): MS (ES+) m/z 446.4 (M+1).

Example 1.49 Synthesis of6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of1′-(diphenylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one(0.29 g, 0.65 mmol) and palladium hydroxide (0.10 g, 20% on activatedcarbon) in acetic acid (20.0 mL) was hydrogenated at 60° C. under normalpressure of hydrogen for 20 hours. The reaction mixture was filteredthrough celite and washed with acetone (50.0 mL). The filtrate wasconcentrated in vacuo to dryness to give the title compound (0.13 g,69%): MS (ES+) m/z 280.2 (M+1).

Example 1.50 Synthesis of1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 1, and making non-criticalvariations using1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (51%) as a white solid: MS (ES+) m/z446.3 (M+1).

Example 1.51 Synthesis of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.49, and makingnon-critical variations using1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (68%): mp 208-210° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.53 (s, 1H), 7.39-6.76 (m, 4H), 6.45 (s, 1H), 6.35 (s, 1H),4.68 (ABq, 2H), 4.45 (t, 2H), 2.92 (t, 2H); MS (ES+) m/z 280.2 (M+1).

Example 1.52 Synthesis of ethyl(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate

A mixture of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]2′(1′H)-one (0.28g, 1.00 mmol), ethyl 2-bromoacetate (0.17 g, 1.00 mmol) and cesiumcarbonate (0.98 g, 3.00 mmol) in acetone (20.0 mL) was stirred at refluxfor 5 hours. After cooling down to ambient temperature, the mixture wasfiltered. The filtrate was evaporated under reduced pressure and theresidue was subjected to column chromatography to give the titlecompound (0.23 g, 63%) as a white solid: MS (ES+) m/z 366.4 (M+1).

Example 1.53 Synthesis of4′-methoxy-1′{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 1, and making non-criticalvariations using3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-4-methoxy-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1.3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (33%) as a white solid: mp 149-153° C.;¹H NMR (300 MHz, DMSO-d₆) δ 7.32-7.24 (m, 1H), 6.82-6.62 (m, 3H), 6.46(s, 1H), 6.40 (d, 1H), 6.08 (s, 1H), 5.87 (ABq, 2H), 4.92 (ABq, 2H),4.82 (ABq, 2H), 3.70 (s, 3H); MS (ES+) m/z 460.3 (M+1).

Example 1.54 Synthesis of7′-fluoro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 1, and making non-criticalvariations using7-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (32%) as a white solid: mp 116-118° C.;¹H NMR (300 MHz, DMSO-d₆) δ 7.36-6.88 (m, 4H), 6.67 (s, 1H), 6.62 (d,1H), 6.19 (s, 1H), 5.90 (d, 2H), 5.07 (q, 2H), 4.75 (dd, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ176.9, 155.8, 154.1, 149.1, 148.8, 145.6, 142.4,140.9, 140.3, 139.2, 139.2, 135.2, 135.2, 128.5, 128.4, 124.9, 128.4,124.9, 124.8, 124.7, 121.2, 120.4, 120.4, 119.8, 117.6, 117.2, 117.0,114.5, 114.5, 109.5, 103.2, 102.0, 93.8, 80.1, 58.3, 58.2, 39.0, 38.9;MS (ES+) m/z 448.3 (M+1).

Example 2 Synthesis of(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)aceticacid

To a suspension of ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate(10.5 g, 24.5 mmol) in THF (200 mL) and water (100 mL) was added lithiumhydroxide monohydrate (3.98 g, 95.0 mmol) at 0° C. The reaction mixturewas stirred at 0° C. for 30 min and at ambient temperature for 17 h. Themixture was neutralized with of 4 M HCl (15.0 mL). The residue obtainedupon removing the solvent was acidified by the addition of 4 M HCl (6.2mL) to pH 3. The solid was filtered, washed with water and hexane, anddried under the reduced pressure to give the title compound (8.48 g,87%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.06 (m, 4H), 6.79(d, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 5.84 (m, 2H), 4.92 (m, 1H),4.69-4.63 (m, 2H), 4.45 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 171.8,155.8, 149.0, 142.4, 141.2, 132.0, 129.0, 124.1, 124.0, 119.2, 108.3,103.4, 101.5, 93.5, 80.2, 58.2, 41.1; MS (ES−) m/z 338.2 (M−1).

Example 2.1 Synthesis of(2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)aceticacid

Following the procedure as described in EXAMPLE 2, and makingnon-critical variations using ethyl(2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)acetateto replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate,the title compound was obtained in 74% yield; MS (ES−) m/z 354 (M−1).

Example 2.2 Synthesis of(4′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid

Following the procedure as described in EXAMPLE 2, and makingnon-critical variations using ethyl(4′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetateto replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate,the title compound was obtained in 92% yield as a colorless solid: mp228-229° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.21 (m, 1H), 7.03 (dd, 1H),6.71 (dd, 1H), 6.52 (s, 1H), 6.36 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m,1H), 4.54-4.51 (m, 3H), 2.95 (t, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8,170.9, 162.1, 162.1, 143.1, 131.7, 130.0, 128.6, 124.7, 119.6, 118.7,117.0, 106.7, 92.8, 77.2, 72.3, 58.1, 41.2, 28.9; MS (ES−) m/z 370.4(M−1).

Example 2.3 Synthesis of(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid

Following the procedure as described in EXAMPLE 2, and makingnon-critical variations using ethyl(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetateto replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate,the title compound was obtained (98%) as a colorless solid: MS (ES−) m/z415.2 (M−1).

Example 2.4 Synthesis of(5′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid

Following the procedure as described in EXAMPLE 2, and makingnon-critical variations using ethyl(5′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetateto replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate,the title compound was obtained in 98% yield as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 7.27-7.25 (m, 1H), 7.16 (d, 1H), 6.72 (d, 1H),6.54 (s, 1H), 6.39 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m, 1H), 4.54-4.51(m, 3H), 2.95 (t, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 170.9, 162.1,162.1, 143.1, 131.7, 130.0, 128.6, 124.7, 119.6, 118.7, 117.0, 106.7,92.8, 77.2, 72.3, 58.1, 41.2, 28.9; MS (ES−) m/z 370.4 (M−1).

Example 2.5 Synthesis of(2-oxo-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-1(2H)-yl)aceticacid

Following the procedure as described in Example 2, and makingnon-critical variations using ethyl(2-oxo-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-1(2H)-yl)acetateto replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate,the title compound was obtained (99%): MS (ES−) m/z 348 (M−1).

Example 2.6 Synthesis of(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid

A mixture of ethyl(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate(0.23 g, 0.63 mmol) and LiOH (0.10 g, 4.20 mmol) in MeOH/H₂O (1/1, 20.0mL) was stirred at ambient temperature for 20 hours. The mixture wasacidified with 0.1 M HCl until pH 2-3. The solid was filtered off anddried to give the title compound (0.15 g, 70%): MS (ES−) m/z 336.3(M−1).

Example 3 Synthesis ofN-(4-chlorobenzyl)-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide

A. Preparation of stock solution of isobutyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetylcarbonate

To a solution of(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)aceticacid (0.30 g, 0.88 mmol) in dichloromethane (12.5 mL) was addedN-methylmorpholine (0.09 g, 0.88 mmol) and iso-butyl chloroformate (0.12g, 0.88 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1.5h and at ambient temperature for 3 h. This mixture was used as a mixedanhydride for the next step amide formation.

B. Synthesis ofN-(4-chlorobenzyl)-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide

To the above mixed anhydride stock solution (2.50 mL, 0.18 mmol) wasadded a solution of 4-chlorobenzylamine in dichloromethane (0.35 mL,0.50 M, 0.18 mmol) at ambient temperature. The reaction mixture wasstirred at ambient temperature for 23 h, washed with saturated aqueoussodium carbonate and water. After removal of the solvent, diethyl etherwas added and the precipitate was collected by filtration to give thetitle compound (0.04 g, 46%): ¹H NMR (300 MHz, CDCl₃) δ 7.39-6.97 (m,8H), 6.49 (s, 1H), 6.29 (br, 1H), 6.01 (s, 1H), 5.85 (m, 2H), 4.87 (m,1H), 4.65 (m, 1H), 4.53-4.29 (m, 4H); MS (ES+), m/z 485.2 (M+23).

Example 3.1

The compounds listed in the following table were synthesized usingsimilar conditions as described in Example 3. The compound numberslisted below do not correspond to the compound numbers provided in thegeneral Reaction Schemes above.

Compound MS Number Name (m/z, M + 1) 1N-(3-fluorophenyl)-2-(2′-oxospiro[furo[2,3- 433.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 2N-butyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 395.2indol]-1′(2′H)-yl)acetamide 31′-(2-oxo-2-piperidin-1-ylethyl)spiro[furo[2,3- 407.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4N-butyl-N-methyl-2-(2′-oxospiro[furo[2,3- 409.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 52-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 415.21′(2′H)-yl)-N-phenylacetamide 6N-(4-fluorophenyl)-2-(2′-oxospiro[furo[2,3- 433.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 7N-(3-fluorobenzyl)-2-(2′-oxospiro[furo[2,3- 447.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 8N-(3-chlorophenyl)-2-(2′-oxospiro[furo[2,3- 449.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 9N-(2-fluorophenyl)-2-(2′-oxospiro[furo[2,3- 433.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 10N-(2-ethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 11N-(4-ethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 12N-(3-methylphenyl)-2-(2′-oxospiro[furo[2,3- 429.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 13N-(2,3-dimethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 14N-(3,5-dimethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 152-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 409.41′(2′H)-yl)-N-pentylacetamide 162-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 381.31′(2′H)-yl)-N-propylacetamide 17N-isopropyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 381.47,3′-indol]-1′(2′H)-yl)acetamide 18N-(3-methylbutyl)-2-(2′-oxospiro[furo[2,3- 409.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 19N-isobutyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 395.37,3′-indol]-1′(2′H)-yl)acetamide 20N-hexyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 423.4indol]-1′(2′H)-yl)acetamide 21N-cyclohexyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 421.47,3′-indol]-1′(2′H)-yl)acetamide 22N-cyclopentyl-2-(2′-oxospiro[furo[2,3- 407.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 23N-heptyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 437.5indol]-1′(2′H)-yl)acetamide 24N-(2-chlorobenzyl)-2-(2′-oxospiro[furo[2,3- 463.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 25N-(2,6-dimethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 26N-(2-methoxyphenyl)-2-(2′-oxospiro[furo[2,3- 445.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 27N-[(5-methyl-2-furyl)methyl]-2-(2′-oxospiro[furo[2,3- 433.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 28N-ethyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 367.4indol]-1′(2′H)-yl)acetamide 29N-methyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 353.37,3′-indol]-1′(2′H)-yl)acetamide 30N-(2-fluorobenzyl)-2-(2′-oxospiro[furo[2,3- 447.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 31N-[2-(3-methoxyphenyl)ethyl]-2-(2′-oxospiro[furo[2,3- 473.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 32N-(2-ethoxyethyl)-2-(2′-oxospiro[furo[2,3- 411.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 33N-(4-methoxybenzyl)-2-(2′-oxospiro[furo[2,3- 459.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 34N-(2,4-dimethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 35N-(3-isopropoxypropyl)-2-(2′-oxospiro[furo[2,3- 439.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 36N-(2-furylmethyl)-2-(2′-oxospiro[furo[2,3- 419.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 37N-(cyclohexylmethyl)-2-(2′-oxospiro[furo[2,3- 435.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 38N-(3-fluoro-2-methylphenyl)-2-(2′-oxospiro[furo[2,3- 447.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 39N-(4-methoxyphenyl)-2-(2′-oxospiro[furo[2,3- 445.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 40N-cyclobutyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 393.47,3′-indol]-1′(2′H)-yl)acetamide 41N-(2,5-difluorophenyl)-2-(2′-oxospiro[furo[2,3- 451.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 42N-benzyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 429.3indol]-1′(2′H)-yl)acetamide 43N-(cyclopropylmethyl)-2-(2′-oxospiro[furo[2,3- 393.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 44N-butyl-N-ethyl-2-(2′-oxospiro[furo[2,3- 423.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 45N-octyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 451.2indol]-1′(2′H)-yl)acetamide 46N-(3,3-dimethylbutyl)-2-(2′-oxospiro[furo[2,3- 423.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 47N-(4-chloro-2-methylphenyl)-2-(2′-oxospiro[furo[2,3- 463.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 48N-(3-methoxyphenyl)-2-(2′-oxospiro[furo[2,3- 445.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 49N-(2-fluoro-4-methylphenyl)-2-(2′-oxospiro[furo[2,3- 447.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 50N-(3,4-dimethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 51N-(3-chlorobenzyl)-2-(2′-oxospiro[furo[2,3- 463.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 52N-(3-methoxybenzyl)-2-(2′-oxospiro[furo[2,3- 459.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 53N-(3,4-difluorophenyl)-2-(2′-oxospiro[furo[2,3- 451.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 54N-(3-methylbenzyl)-2-(2′-oxospiro[furo[2,3- 443.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 55N-(2-methoxybenzyl)-2-(2′-oxospiro[furo[2,3- 459.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 56N-(4-isopropylphenyl)-2-(2′-oxospiro[furo[2,3- 457.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 57N-(2,3-difluorophenyl)-2-(2′-oxospiro[furo[2,3- 451.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 582-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 423.11′(2′H)-yl)-N-(tetrahydrofuran-2-ylmethyl)acetamide 59N-[2-(4-methylphenyl)ethyl]-2-(2′-oxospiro[furo[2,3- 457.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 60N-[2-(3-chlorophenyl)ethyl]-2-(2′-oxospiro[furo[2,3- 477.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 61N-(4-cyanophenyl)-2-(2′-oxospiro[furo[2,3- 440.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 62N-(2,3-dihydro-1H-inden-1-yl)-2-(2′-oxospiro[furo[2,3- 455.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 63N-(2-methoxyethyl)-2-(2′-oxospiro[furo[2,3- 397.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 64N-[2-(4-methoxyphenyl)ethyl]-2-(2′-oxospiro[furo[2,3- 473.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 65N-(2-cyanoethyl)-2-(2′-oxospiro[furo[2,3- 392.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 66N-(2,4-dichlorobenzyl)-2-(2′-oxospiro[furo[2,3- 497.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 67N-(3,5-difluorobenzyl)-2-(2′-oxospiro[furo[2,3- 465.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 68N-(2,4-difluorobenzyl)-2-(2′-oxospiro[furo[2,3- 465.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 69N-(2-methylbenzyl)-2-(2′-oxospiro[furo[2,3- 443.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 70N-(3,4-difluorobenzyl)-2-(2′-oxospiro[furo[2,3- 465.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 71N-(2,5-difluorobenzyl)-2-(2′-oxospiro[furo[2,3- 465.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 722-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 423.21′(2′H)-yl)-N,N-dipropylacetamide 73N,N-dibutyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 451.27,3′-indol]-1′(2′H)-yl)acetamide 74N-(2,6-difluorobenzyl)-2-(2′-oxospiro[furo[2,3- 465.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 75N-[2-(methylthio)phenyl]-2-(2′-oxospiro[furo[2,3- 461.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 76N-(2-isopropylphenyl)-2-(2′-oxospiro[furo[2,3- 457.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 77N-(4-bromophenyl)-2-(2′-oxospiro[furo[2,3- 493.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 78N-(4-chlorophenyl)-2-(2′-oxospiro[furo[2,3- 449.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 79N-(2,4-dichlorophenyl)-2-(2′-oxospiro[furo[2,3- 483.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 80N-(3,5-dichlorophenyl)-2-(2′-oxospiro[furo[2,3- 483.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 81N,N-diethyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 395.17,3′-indol]-1′(2′H)-yl)acetamide 82N-methyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 429.17,3′-indol]-1′(2′H)-yl)-N-phenylacetamide 83N-(4-hydroxybutyl)-2-(2′-oxospiro[furo[2,3- 411.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 84N-allyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 379.1indol]-1′(2′H)-yl)acetamide 85N-(2-fluoro-5-methylphenyl)-2-(2′-oxospiro[furo[2,3- 447.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 86N-(1,3-benzodioxol-5-ylmethyl)-2-(2′-oxospiro[furo[2,3- 473.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 87N-cyclopropyl-2-(2′-oxospiro[furo[2,3- 379.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 88N-(2-cyclopropylethyl)-2-(2′-oxospiro[furo[2,3- 407.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 89N-(3,4-dichlorobenzyl)-2-(2′-oxospiro[furo[2,3- 497.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 90N-(2,3-dichlorobenzyl)-2-(2′-oxospiro[furo[2,3- 497.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 91N-(2,5-dimethylphenyl)-2-(2′-oxospiro[furo[2,3- 443.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 92N-(3,4-dichlorophenyl)-2-(2′-oxospiro[furo[2,3- 483.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 93N,N-dimethyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 367.27,3′-indol]-1′(2′H)-yl)acetamide 94N-methyl-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 457.27,3′-indol]-1′(2′H)-yl)-N-(2-phenylethyl)acetamide 952-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 457.21′(2′H)-yl)-N-(2-phenylpropyl)acetamide 96N-[(1R)-1-cyclohexylethyl]-2-(2′-oxospiro[furo[2,3- 449.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 97N-[(1S)-1-cyclohexylethyl]-2-(2′-oxospiro[furo[2,3- 449.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 982-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 451.41′(2′H)-yl)-N-(2-piperidin-1-ylethyl)acetamide 992-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 483.11′(2′H)-yl)-N-[3-(trifluoromethyl)phenyl]acetamide 100N-(3-cyanophenyl)-2-(2′-oxospiro[furo[2,3- 440.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 1011′-(2-morpholin-4-yl-2-oxoethyl)spiro[furo[2,3- 409.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1022-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 443.11′(2′H)-yl)-N-(2-phenylethyl)acetamide 103N-(4-bromo-2-chlorophenyl)-2-(2′-oxospiro[furo[2,3- 527.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide 104N-(2-biphenyl-4-ylethyl)-2-(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetamide

Example 3.2 Synthesis ofN-(2-fluorophenyl)-2-(2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)acetamide

To a solution of2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)aceticacid (0.18 g, 0.54 mmol) in chloroform (5.00 mL) was added oxalylchloride (0.09 mL, 1.07 mmol) with one drop of DMF. The mixture wasrefluxed for 2 hours, and evaporated under reduced vacuum to dryness. Tothe above residue were added Et₃N (0.66 mL, 4.72 mmol), 2-fluoroaniline(0.10 mL, 1.00 mmol) and THF (5.00 mL). The reaction mixture was stirredat ambient temperature overnight, evaporated to dryness. The residue wassubjected to column chromatography (25% ethyl acetate in hexane) toyield the title compound (0.04 g, 17%): ¹H NMR (300 MHz, CDCl₃) δ 8.26(t, 1H), 8.05-7.90 (br, 1H), 7.33 (td, 1H), 7.26-6.96 (m, 6H), 6.83 (s,1H), 6.61 (s, 1H), 4.98 (d, 1H), 4.73 (d, 1H), 4.71 (d, 1H), 4.52 (d,1H), 2.85 (t, 2H), 2.69 (t, 2H), 2.12-1.94 (m, 2H); ¹³C NMR (75 MHz,CDCl₃) δ 178.6, 165.0, 159.8, 146.9, 141.5, 137.5, 132.5, 129.2, 126.3,125.2, 124.8, 124.4, 124.3, 121.9, 118.9, 115.2, 114.9, 109.0, 106.8,79.9, 58.2, 45.3, 33.2, 32.0, 26.1; MS (ES+) m/z 429 (M+1), 451 (M+23).

Example 3.3 Synthesis ofN-(2-fluorophenyl)-2-(2-oxo-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-1(2H)-yl)acetamide

Following the procedure as described in EXAMPLE 3.2, and makingnon-critical variations using(2-oxo-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-1(2H)-yl)aceticacid to replace2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained in 5% yield: ¹H NMR (300 MHz,CDCl₃) δ 8.27 (t, 1H), 8.04-7.90 (br, 1H), 7.33 (td, 1H), 7.26-6.97 (m,6H), 6.69 (s, 1H), 6.48 (s, 1H), 4.94 (d, 1H), 4.69 (d, 1H), 4.71 (d,1H), 4.52 (d, 1H), 2.81-2.45 (m, 4H), 1.82-1.60 (m, 4H); MS (ES+) m/z443 (M+1), 465 (M+23).

Example 3.4 Synthesis of2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

A. Synthesis of(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid

Following the procedure as described in EXAMPLE 2, and makingnon-critical variations using ethyl(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetateto replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate,the title compound was obtained in 100% yield. The product was useddirectly in the next step.

B. Synthesis of2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

To a solution of(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid (0.24 g, 0.59 mmol) and oxalyl chloride (0.15 mL, 1.76 mmol) intoluene (7.00 mL) was added one drop of DMF and the resulted mixture wasstirred at ambient temperature overnight. The mixture was concentratedunder vacuum. The residue was dissolved in dichloromethane (5.00 mL) and2-fluoroaniline (0.18 mL, 1.89 mmol) was added at ambient temperature.The mixture was stirred at ambient temperature for one hour. Moredichloromethane (100 mL) was added. The organic layer was washed withwater, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/5) to give the title compound(0.23 g, 76%): ¹H NMR (300 MHz, CDCl₃) δ 8.20 (t, 1H), 7.80 (br, 1H),7.27-7.17 (m, 2H), 7.16-7.03 (m, 3H), 6.97-6.88 (m, 1H), 6.78-6.60 (m,2H), 5.08 (d, 1H), 4.93 (d, 1H), 4.68 (d, 1H), 4.49 (d, 1H); ¹³C NMR (75MHz, CDCl₃) δ 177.1, 163.9, 157.8, 143.6, 131.0, 128.8, 128.1, 124.7,121.8, 120.0, 115.0, 111.6, 108.1, 99.8, 77.5, 59.2, 44.7; MS (ES+) m/z503.4 (M+1), 505.4 (M+1).

Example 3.5 Synthesis of2-(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

A. Synthesis of(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid

Following the procedure as described in EXAMPLE 2, and makingnon-critical variations using ethyl(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetateto replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate,the title compound was obtained. The product was used directly in thenext step.

B. Synthesis of2-(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (61% for two steps): MS (ES+) m/z537.4 (M+1), 539.4 (M+1).

Example 3.6 Synthesis of2-(4′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(4′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (69%) as a colorless solid: mp243-245° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.19 (t, 1H), 7.96 (s, 1H),7.21-7.27 (m, 1H), 7.10-7.02 (m, 4H), 6.88 (d, 1H), 6.55 (s, 1H), 6.35(s, 1H), 4.96 (dd, 2H), 4.70 (d, 1H), 4.57-4.53 (m, 3H), 2.97 (t, 2H);¹³C NMR (75 MHz, CDCl₃) δ 178.2, 164.4, 162.2, 162.1, 143.2, 131.6,130.2, 128.5, 125.2, 125.1, 124.9, 124.6, 121.9, 119.7, 118.6, 116.8,115.1, 114.8, 107.3, 92.9, 77.2, 72.4, 58.2, 44.9, 28.9; MS (ES+) m/z465.5 (M+1).

Example 3.7 Synthesis of2-(5′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(5′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (91%) as a colorless solid: mp229-230° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.21 (t, 1H), 7.88 (s, 1H),7.28-7.25 (m, 1H), 7.18 (d, 1H), 7.13-7.04 (m, 3H), 6.90 (d, 1H), 6.57(s, 1H), 6.40 (s, 1H), 4.95 (d, 1H), 4.70-4.66 (m, 2H), 4.56-4.43 (m,3H), 2.99 (t, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 170.9, 162.1, 162.1,143.1, 131.7, 130.0, 128.6, 124.7, 119.6, 118.7, 117.0, 106.7, 92.8,77.2, 72.3, 58.1, 41.2, 28.9; MS (ES+) m/z 465.4 (M+1).

Example 3.8 Synthesis of2-(6-chloro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(6-chloro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetic acid toreplace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (10%) as a white solid: mp 70-75°C.; ¹H NMR (300 MHz, CDCl₃) δ 8.21 (t, 1H), 7.99 (br, 1H), 7.32 (dt,1H), 7.19-6.93 (m, 7H), 6.80 (dd, 1H), 6.73 (d, 1H), 5.01 (d, 1H), 4.75(d, 1H), 4.69 (d, 1H), 4.50 (d, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.7,164.6, 161.4, 141.4, 135.5, 131.6, 129.4, 127.3, 125.2, 125.0, 124.7,124.6, 124.4, 124.3, 124.1, 121.9, 121.8, 115.1, 114.8, 111.3, 109.0,80.3, 57.6, 44.9; MS (ES+) m/z 423.4 (M+1).

Example 3.9 Synthesis of2-(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (35%) as a white solid: mp 97-100°C.; ¹H NMR (300 MHz, CDCl₃) δ 8.20-8.10 (m, 2H), 7.31 (dt, 1H),7.19-7.00 (m, 5H), 6.95 (d, 1H), 6.77-6.40 (m, 2H), 5.02 (d, 1H), 4.74(d, 1H), 4.69 (d, 1H), 4.51 (d, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4,164.3, 141.4, 131.2, 129.7, 125.6, 125.5, 125.3, 125.2, 125.1, 124.7,124.4, 124.1, 121.8, 115.1, 114.9, 112.1, 111.8, 109.1, 100.3, 100.0,80.7, 57.9; MS (ES+) m/z 425.5 (M+1).

Example 3.10 Synthesis of2-(5-bromo-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(5-bromo-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetic acid toreplace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (94%) as a light yellow solid: mp100-103° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.26 (dd, 1H), 7.92 (br, 1H),7.39-7.31 (m, 2H), 7.22-7.01 (m, 6H), 6.91 (d, 1H), 6.87 (d, 1H), 5.02(d, 1H), 4.76 (d, 1H), 4.67 (d, 1H), 4.57 (d, 1H); MS (ES+) m/z 467.3(M+1).

Example 3.11 Synthesis of2-(4′-fluoro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(4′-fluoro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained: ¹H NMR (300 MHz, CDCl₃) δ 8.20(t, 1H), 7.91 (s, 1H), 7.29 (dt, 1H), 7.13-7.04 (m, 3H), 6.81-6.75 (m,2H), 6.61 (s, 1H), 6.39 (s, 1H), 4.95-4.87 (m, 2H), 4.70 (d, 1H),4.55-4.44 (m, 3H), 2.98 (t, 2H); MS (ES+) m/z 449.5 (M+1)

Example 3.12 Synthesis of2-(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (75%) as a colorless solid: mp245-246° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.20 (t, 1H), 7.90 (s, 1H),7.20-7.03 (m, 5H), 6.92 (dd, 1H), 6.53 (s, 1H), 6.36 (s, 1H), 5.05 (d,1H), 4.90 (d, 1H), 4.69 (d, 1H), 4.55-4.43 (m, 3H), 2.97 (t, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 178.3, 164.3, 162.4, 162.2, 143.4, 130.4, 130.0,128.0, 125.5, 125.2, 124.7, 121.9, 120.0, 119.7, 118.6, 116.7, 115.1,114.8, 107.8, 92.8, 77.2, 72.4, 59.1, 44.9, 28.9; MS (ES+) m/z 509(M+1), 511 (M+1).

Example 3.13 Synthesis ofN-(2-fluorophenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 3.4B, and makingnon-critical variations using(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (68%) as a white solid: mp210-212° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.17-7.67 (m,1H), 7.55-6.90 (m, 7H), 6.54 (s, 1H), 6.38 (s, 1H), 4.68 (m, 4H), 4.46(t, 2H), 2.93 (t, 2H); MS (ES+) m/z 431.4 (M+1).

Example 3.14 Synthesis of2-(4′-fluoro-7′-methyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 3.4B and makingnon-critical variations using(4′-fluoro-7′-methyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid to replace(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)aceticacid, the title compound was obtained (21%) as a white solid: mp250-255° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.23 (s, 1H), 7.99-7.69 (m,1H), 7.36-7.01 (m, 4H), 6.74 (t, 1H), 6.63 (s, 1H), 6.42 (s, 1H), 5.90(d, 2H), 4.88 (t, 2H), 4.76 (ABq, 2H), 3.30 (s, 3H); MS (ES+) m/z 463.4(M+1).

Example 4 Synthesis of4′-[6-(dimethylamino)pyridin-3-yl]-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To an oven-dried flask was charged with[6-(dimethylamino)pyridin-3-yl]boronic acid (37.0 mg, 0.17 mmol),Pd(PPh₃)₄ (13.5 mg, 0.012 mmol) followed by flashing with nitrogen. Tothe flask was added a solution of4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(50.0 mg, 0.12 mmol) in anhydrous dioxane (2.00 mL) followed by theaddition of 2.0 M Na₂CO₃ (0.24 mL). The reaction mixture was heated atreflux for 48 h. After cooling down to ambient temperature, the solventwas removed under reduced pressure. The residue was diluted with ethylacetate (2.00 mL), washed with saturated ammonium chloride (2.00 mL),and concentrated in vacuo to dryness. The residue was subjected tocolumn chromatography to yield the title compounds: ¹H NMR (300 MHz,CDCl₃) δ 7.77 (d, 1H), 7.32 (t, 1H), 6.87 (dd, 2H), 6.71 (dd, 1H), 6.23(d, 1H), 6.20 (s, 1H), 5.88 (d, 2H), 4.56 (ABq, 2H), 3.89-3.80 (m, 1H),3.69-3.59 (m, 1H), 3.05 (s, 6H), 1.78-1.69 (m, 2H), 1.39-1.35 (m, 4H),0.90 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.9, 158.3, 156.1, 148.8,147.3, 142.9, 142.0, 137.8, 137.2, 129.9, 128.9, 125.6, 122.0, 121.0,107.6, 104.3, 102.5, 101.5, 93.6, 77.8, 58.5, 40.5, 38.2, 29.1, 27.2,22.4, 14.0; MS (ES+, m/z) 472.0 (M+1).

Example 4.1

The compounds listed in the following table were synthesized usingsimilar conditions as described in Example 4. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

MS Com- (m/z, pound M + Number Name 1) 1054′-(3,5-dimethoxyphenyl)-1′-pentylspiro[furo[2,3- 488.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1064′-(4-fluorophenyl)-1′-pentylspiro[furo[2,3- 447.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1074′-(3,5-dichlorophenyl)-1′-pentylspiro[furo[2,3- 496.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1084′-[4-(dimethylamino)phenyl]-1′-pentylspiro[furo[2,3- 471.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1091′-pentyl-4′-(3,4,5-trimethoxyphenyl)spiro[furo[2,3- 518.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1104-(2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3- 453.3f][1,3]benzodioxole-7,3′-indol]-4′-yl)benzonitrile 1114′-dibenzo[b,d]furan-4-yl-1′-pentylspiro[furo[2,3- 518.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1124′-(1-benzyl-1H-pyrazol-4-yl)-1′-pentylspiro[furo[2,3- 508.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1134′-(2-methoxypyrimidin-5-yl)-1′-pentylspiro[furo[2,3- 460.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1144′-(2,4-dimethoxypyrimidin-5-yl)-1′- 490.4pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1154-(2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3- 471.3f][1,3]benzodioxole-7,3′-indol]-4′-yl)benzamide 1164′-{4-[(dimethylamino)methyl]phenyl}-1′- 484.6pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1174′-(1-benzofuran-2-yl)-1′-pentylspiro[furo[2,3- 467.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1184′-(6-methoxypyridin-3-yl)-1′-pentylspiro[furo[2,3- 458.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 119N,N-dimethyl-4-(2′-oxo-1′-pentyl-1′,2′- 498.6dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-4′-yl)benzamide120 4′-dibenzo[b,d]thien-4-yl-1′-pentylspiro[furo[2,3- 533.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1213-(2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3- 452.5f][1,3]benzodioxole-7,3′-indol]-4′-yl)benzonitrile 1221′-pentyl-4′-pyridin-3-ylspiro[furo[2,3- 428.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1234′-(3-fluoro-4-methoxyphenyl)-1′-pentylspiro[furo[2,3- 475.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1241′-pentyl-4′-[2-(trifluoromethoxy)phenyl]spiro[furo[2,3- 511.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1254′-[3,5-bis(trifluoromethyl)phenyl]-1′- 563.5pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1261′-pentyl-4′-[4-(trifluoromethyl)pyridin-3- 496.5yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one 1274′-(2-fluoro-5-methoxyphenyl)-1′-pentylspiro[furo[2,3- 475.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1284′-(4-ethoxy-3-fluorophenyl)-1′-pentylspiro[furo[2,3- 489.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1294′-(1-benzothien-2-yl)-1′-pentylspiro[furo[2,3- 483.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1304′-isobutyl-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole- 407.57,3′-indol]-2′(1′H)-one 1311′-pentyl-4′-[4-(trifluoromethoxy)phenyl]spiro[furo[2,3- 511.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1324′-(5-fluoro-2-methoxyphenyl)-1′-pentylspiro[furo[2,3- 475.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1334′-(1,3-benzodioxol-5-yl)-1′-pentylspiro[furo[2,3- 471.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1341′-pentyl-4′-phenylspiro[furo[2,3-f][1,3]benzodioxole- 427.57,3′-indol]-2′(1′H)-one 1351′-pentyl-4′-[2-(trifluoromethyl)phenyl]spiro[furo[2,3- 495.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1364′-(4-chlorophenyl)-1′-pentylspiro[furo[2,3- 461.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1374′-(2,3-dihydro-1,4-benzodioxin-6-yl)-1′- 485.5pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1381′-pentyl-4′-quinolin-3-ylspiro[furo[2,3- 478.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1394′-(3,5-difluorophenyl)-1′-pentylspiro[furo[2,3- 463.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1404′-isoquinolin-4-yl-1′-pentylspiro[furo[2,3- 478.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1414′-(6-methoxypyridin-2-yl)-1′-pentylspiro[furo[2,3- 458.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1424′-(1H-indol-5-yl)-1′-pentylspiro[furo[2,3- 466.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 143N-[2-(2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3- 484.5f][1,3]benzodioxole-7,3′-indol]-4′- yl)phenyl]acetamide 1444′-(4-fluoro-2-methylphenyl)-1′-pentylspiro[furo[2,3- 459.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1451′-pentyl-4′-quinolin-6-ylspiro[furo[2,3- 478.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 146N-[4-(2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3- 520.6f][1,3]benzodioxole-7,3′-indol]-4′- yl)phenyl]methanesulfonamide 1474′-(5-chloro-2-methoxyphenyl)-1′-pentylspiro[furo[2,3- 492.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1481′-pentyl-4′-[3-(trifluoromethoxy)phenyl]spiro[furo[2,3- 511.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1491′-pentyl-4′-(4-phenoxyphenyl)spiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1504′-(2,4-dimethoxyphenyl)-1′-pentylspiro[furo[2,3- 487.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1514′-(3-furyl)-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole- 417.57,3′-indol]-2′(1′H)-one 1524′-(3,4-dimethoxyphenyl)-1′-pentylspiro[furo[2,3- 487.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 153N-[4-(2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3- 484.5f][1,3]benzodioxole-7,3′-indol]-4′- yl)phenyl]acetamide 1541′-pentyl-4′-[(E)-2-phenylvinyl]spiro[furo[2,3- 453.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1554′-(4-methoxyphenyl)-1′-pentylspiro[furo[2,3- 457.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1564′-(6-fluoropyridin-3-yl)-1′-pentylspiro[furo[2,3- 446.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1574′-(3-chloro-4-fluorophenyl)-1′-pentylspiro[furo[2,3- 479.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1584′-(3-chlorophenyl)-1′-pentylspiro[furo[2,3- 461.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1594′-(1-benzothien-3-yl)-1′-pentylspiro[furo[2,3- 483.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1601′-pentyl-4′-(2-phenoxyphenyl)spiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1614′-(4-isopropoxyphenyl)-1′-pentylspiro[furo[2,3- 485.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1624′-[(E)-2-(4-fluorophenyl)vinyl]-1′-pentylspiro[furo[2,3- 471.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1634′-(6-fluoropyridin-2-yl)-1′-pentylspiro[furo[2,3- 446.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1641′-pentyl-4′-[1-(phenylsulfonyl)-1H-indol-3- 606.7yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one 1654′-(3-fluorophenyl)-1′-pentylspiro[furo[2,3- 445.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1664′-(3-acetylphenyl)-1′-pentylspiro[furo[2,3- 469.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1674′-(2-furyl)-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole- 417.57,3′-indol]-2′(1′H)-one 168 4′-(4-methylphenyl)-1′-pentylspiro[furo[2,3-441.5 f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1694′-(1-methyl-1H-pyrrol-3-yl)-1′-pentylspiro[furo[2,3- 430.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1704′-(2,5-difluorophenyl)-1′-pentylspiro[furo[2,3- 463.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1714′-(2-fluorophenyl)-1′-pentylspiro[furo[2,3- 445.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1724′-(2-chlorophenyl)-1′-pentylspiro[furo[2,3- 461.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1734′-(2,4-difluorophenyl)-1′-pentylspiro[furo[2,3- 463.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1744′-(4-morpholin-4-ylphenyl)-1′-pentylspiro[furo[2,3- 512.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 175 tert-butyl5-methoxy-3-(2′-oxo-1′-pentyl-1′,2′- 596.7dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-4′-yl)-1H-indole-1-carboxylate 1761′-pentyl-4′-pyrimidin-5-ylspiro[furo[2,3- 429.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 177 tert-butyl4-[2-(2′-oxo-1′-pentyl-1′,2′- 611.7dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-4′-yl)phenyl]piperazine-1-carboxylate 1784′-(2-methoxypyridin-3-yl)-1′-pentylspiro[furo[2,3- 458.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1794′-(5-methoxypyridin-3-yl)-1′-pentylspiro[furo[2,3- 458.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1804′-(4-butoxy-3-fluorophenyl)-1′-pentylspiro[furo[2,3- 517.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1811′-pentyl-4′-pyridin-4-ylspiro[furo[2,3- 428.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1821′-pentyl-4′-phenoxathiin-4-ylspiro[furo[2,3- 549.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1834′-[(1Z)-3-chloroprop-1-en-1-yl]-1′- 425.9pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1841′-pentyl-4′-(3-thienyl)spiro[furo[2,3- 433.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1854′-(2,3-dimethoxyphenyl)-1′-pentylspiro[furo[2,3- 487.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1864′-(4-butylphenyl)-1′-pentylspiro[furo[2,3- 483.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1874′-(3-fluoro-5-methoxyphenyl)-1′-pentylspiro[furo[2,3- 475.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1884′-[3-fluoro-4-(pentyloxy)phenyl]-1′- 531.6pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1894′-(2-butoxy-5-fluorophenyl)-1′-pentylspiro[furo[2,3- 517.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1904′-(3-butoxyphenyl)-1′-pentylspiro[furo[2,3- 499.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1914′-(4-butoxyphenyl)-1′-pentylspiro[furo[2,3- 499.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1924′-(4-isobutoxyphenyl)-1′-pentylspiro[furo[2,3- 499.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1934′-{2-chloro-4-[(3,5-dimethoxybenzyl)oxy]phenyl}-1′- 628.1pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1944′-[4-(benzyloxy)-3-chlorophenyl]-1′- 568.1pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 1954′-(1-methyl-1H-indol-5-yl)-1′-pentylspiro[furo[2,3- 480.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1964′-(4-methoxypyridin-3-yl)-1′-pentylspiro[furo[2,3- 458.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1974′-[(6-methoxypyridin-3-yl)amino]-1′- 473.5pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one

Example 4.2 Synthesis of2-(5,6-difluoro-2′-oxo-4′-pyrimidin-5-ylspiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

To a solution of2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide (0.15 g, 0.30 mmol) in anhydrous1,4-dioxane (5.00 mL) was added Pd(PPh₃)₄ (0.03 g, 0.03 mmol) andstirred at ambient temperature for 10 min. Pyrimidine-5-boronic acid(0.06 g, 0.45 mmol) and sodium carbonate (0.90 mL of 2 M solution, 1.80mmol) were added. The reaction mixture was reluxed at 120° C. for 16 h,diluted with ethyl acetate (50.0 mL). The organic layer was washed withwater, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/1) to give the title compound(0.13 g, 84%): ¹H NMR (300 MHz, CDCl₃) δ 9.13 (s, 1H), 8.29-8.10 (m,3H), 7.62 (s, 1H), 7.44 (t, 1H), 7.16-7.03 (m, 4H), 6.91 (d, 1H),6.85-6.76 (m, 1H), 6.46-6.37 (m, 1H), 4.85-4.73 (m, 2H), 4.61-4.47 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.1, 163.9, 157.7, 156.4, 155.7, 141.9,132.9, 130.0, 126.0, 124.7, 121.9, 115.0, 111.6, 109.8, 100.2, 79.4,57.9, 44.7; MS (ES+) m/z 503.5 (M+1).

Example 4.3 Synthesis of2-(6,6-dimethyl-2′-oxo-4′-pyrimidin-5-y1-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide

Following the procedure as described in EXAMPLE 4.2, making variationusing2-(4′-bromo-6,6-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1(2′H)-yl)-N-(2-fluorophenyl)acetamideto replace2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide,the title compound was obtained (95%): mp>250° C.; ¹H NMR (300 MHz,CDCl₃) δ 9.10 (s, 1H), 8.24 (t, 1H), 8.15 (s, 2H), 8.00 (s, 1H), 7.40(t, 1H), 7.16-7.03 (m, 4H), 6.88 (d, 1H), 6.61 (s, 1H), 5.99 (s, 1H),4.84-4.73 (m, 2H), 4.54 (d, 1H), 4.44 (d, 1H), 2.79 (s, 2H), 1.45 (s,3H), 1.39 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.4, 164.5, 161.1, 157.4,155.8, 154.1, 150.8, 141.7, 132.9, 132.2, 131.3, 129.4, 125.9, 125.5,125.2, 124.7, 121.9, 120.8, 119.3, 118.8, 115.0, 109.5, 93.5, 88.5,78.9, 58.0, 45.0, 42.0, 28.0, 27.9; MS (ES+) m/z 537.5 (M+1).

Example 4.4 Synthesis of4′-(3-furyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, making variationsusing 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and 3-furanboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (66%) as a colorless solid: mp 270-272° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.32 (t, 1H), 7.25 (d, 2H), 6.97 (d, 1H), 6.91 (d, 1H), 6.83(s, 1H), 6.44 (s, 1H), 6.30 (s, 1H), 6.04 (d, 1H), 5.89 (dd, 2H), 4.68(ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 180.4, 156.2, 149.2, 142.9, 142.1,141.2, 140.4, 131.3, 129.2, 128.5, 125.3, 122.6, 120.6, 111.0, 109.5,102.9, 101.6, 94.0, 77.2, 59.0; MS (ES+) m/z 348.4 (M+1).

Example 4.5 Synthesis of4′-dibenzo[b,d]furan-4-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and dibenzo[b,d]furan-4-ylboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (10%) as a colorless solid: mp >230° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.77 (s, 1H), 8.04 (d, 1H), 7.97 (dd, 1H), 7.43-7.42 (m,3H), 7.34-7.29 (m, 3H), 7.16 (t, 1H), 6.98 (d, 1H), 6.89 (d, 1H), 6.25(s, 1H), 5.69 (d, 2H), 4.41 (ABq, 2H); MS (ES+) m/z 448.5 (M+1).

Example 4.6 Synthesis of4′-(6-methoxypyridin-3-yl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (6-methoxypyridin-3-yl)boronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (51%) as a colorless solid: mp 174-176° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.73 (d, 1H), 7.69 (d, 1H), 7.34 (t, 1H), 7.03 (d, 1H),6.89-6.86 (m, 2H), 6.65 (d, 1H), 6.61 (d, 1H), 6.56 (d, 1H), 6.17 (d,2H), 5.87 (d, 2H), 4.99 (ABq, 2H), 4.56 (ABq, 2H), 3.90 (s, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 177.7, 163.5, 158.4, 156.1, 151.8, 151.8, 149.2,147.8, 146.1, 142.3, 141.6, 138.8, 136.9, 132.6, 130.0, 129.1, 127.8,127.2, 126.2, 119.9, 112.7, 112.7, 110.9, 109.6, 109.5, 108.5, 102.3,101.6, 93.6, 78.2, 58.5, 53.6, 37.0; MS (ES+) m/z 537.4 (M+1).

Example 4.7 Synthesis of4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound wasobtained (37%) as a colorless solid: mp 174-176° C.; MS (ES+) m/z 550.4(M+1).

Example 4.8 Synthesis of4′-pyrimidin-5-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace4′-bromo-1-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and pyrimidin-5-ylboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (32%) as a colorless solid: mp 185-187° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.85 (s, 1H), 9.02 (s, 1H), 8.19 (s, 2H), 7.33 (t, 1H), 7.00(d, 1H), 6.83 (d, 1H), 6.37 (s, 1H), 6.19 (s, 1H), 5.89 (d, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ 178.7, 157.5, 156.0, 155.6, 148.8, 142.3, 133.1,132.6, 131.8, 129.5, 124.5, 120.3, 110.9, 103.2, 101.9, 93.3, 79.5,66.8, 58.5; MS (ES+) m/z 360.4 (M+1).

Example 4.9 Synthesis of4′-(3-furyl)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and 3-furanboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (75%) as a colorless solid: mp 195-197° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.58 (d, 1H), 7.68 (t, 1H), 7.32-7.21 (m, 4H), 6.97 (d, 1H),6.92 (d, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 5.99 (s, 1H),5.12 (ABq, 2H), 4.71 (ABq, 2H), 4.57 (t, 2H), 3.03 (t, 2H); MS (ES+) m/z437.4 (M+1).

Example 4.10 Synthesis of1′-(pyridin-2-ylmethyl)-4′-pyrimidin-5-yl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and pyrimidin-5-ylboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (16%) as a colorless solid: mp>200° C.; ¹H NMR (300 MHz, CDCl₃)δ 9.09 (s, 1H), 8.59 (d, 1H), 8.14 (s, 2H), 7.74 (t, 1H), 7.67 (d, 1H),7.63 (d, 1H), 7.52 (d, 1H), 7.47-7.42 (m, 1H), 7.37 (d, 1H), 7.30 (d,1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.62 (s, 1H), 6.07 (s, 1H), 5.18 (ABq,2H), 4.62 (ABq, 2H), 4.62-4.48 (m, 2H), 3.02 (t, 2H); MS (ES+) m/z 449.5(M+1).

Example 4.11 Synthesis of4′-pyridin-3-yl-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and pyridin-3-ylboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (9%) as a colorless solid: mp>200° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.52 (d, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.79 (t, 1H), 7.40(d, 1H), 7.29 (t, 2H), 7.18-7.08 (m, 2H), 7.00 (d, 1H), 6.81 (d, 1H),6.72 (s, 1H), 5.98 (s, 1H), 5.08 (ABq, 2H), 4.56-4.40 (m, 4H), 3.10-2.90(m, 2H); MS (ES+) m/z 448.5 (M+1).

Example 4.12 Synthesis of4′-(3-furyl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and 3-furylboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (27%) as a colorless solid: mp 167-169° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.34-7.29 (m, 2H), 7.01 (dd, 1H), 6.95 (dd, 1H), 6.77 (dd, 1H),6.74 (dd, 1H), 6.51 (s, 1H), 6.41 (d, 1H), 6.34 (s, 1H), 6.00 (dd, 1H),4.97 (ABq, 2H), 4.67 (ABq, 2H), 4.56 (t, 2H), 3.01 (t, 2H); MS (ES+) m/z494.4 (M+1).

Example 4.13 Synthesis of4′-quinolin-3-yl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,quinolin-3-ylboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (50%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.52 (d,1H), 8.09 (d, 1H), 7.74-7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.42-7.39 (m,2H), 7.32 (s, 1H), 7.09 (d, 1H), 7.01 (d, 1H), 6.78-6.77 (m, 1H), 6.45(d, 1H), 6.26 (s, 1H), 5.94 (d, 1H), 5.91 (s, 1H), 5.89 (d, 1H), 5.03(ABq, 2H), 4.52 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 156.0,151.8, 150.0, 149.3, 147.0, 142.4, 141.8, 136.8, 135.8, 131.1, 130.2,129.9, 129.3, 129.0, 128.8, 128.0, 127.1, 127.0, 126.4, 126.0, 120. 4,112.7, 109.5, 108.8, 102.5, 101.7, 93.7, 78.3, 58.5, 37.1; MS (ES+) m/z557.4 (M+1).

Example 4.14 Synthesis of4′-pyrimidin-5-yl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.11 g, 0.21 mmol), pyrimidine-5-boronic acid (0.04 g, 0.33 mmol),tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol), 2.00 Msodium carbonate (1.00 mL) and 1,2-dimethoxyethane (10.0 mL) was heatedat reflux for 16 h under nitrogen. After the organic solvent wasevaporated in vacuo, the black residue was extracted with ethyl acetate(3×35.0 mL). The combined organic layers was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was subjected to column chromatography eluting with ethylacetate:hexane (35%) to afford the title compound (0.03 g, 26%): mp263-266° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.10 (s, 1H), 8.14 (s, 2H), 7.39(t, 1H), 7.10, (d, 1H), 6.87 (d, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.46(s, 1H), 6.07 (s, 1H), 5.03 (ABq, 2H), 4.62-4.48 (m, 2H), 4.58 (ABq,2H), 3.01 (t, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.3, 162.5, 161.0, 157.4,155.9, 151.6, 142.2, 141.7, 132.8, 132.3, 131.3, 129.3, 125.7, 120.6,120.2, 118.3, 117.0, 112.7, 109.7, 109.4, 93.5, 78.9, 72.5, 57.7, 37.1,28.9; MS (ES+) m/z 506.5 (M+1).

Example 4.15 Synthesis of tert-butyl4-[(2′-oxo-4′-pyrimidin-5-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate

Following the procedure as described in EXAMPLE 4.14, and makingnon-critical variations using tert-butyl4-[(4′-bromo-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)yl)methyl]piperidine-1-carboxylateto replace4′-bromo-1-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (91%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ 9.13 (s, 1H), 8.23 (s, 2H), 8.24-7.37 (m, 5H), 7.01 (d,1H), 6.85 (d, 1H), 6.14 (dd2H), 5.91 (d, 2H), 4.55 (ABq, 2H), 4.15 (d,2H), 3.84-3.58 (m, 3H), 2.69 (t, 2H), 1.44 (s, 9H); MS (ES+) m/z 557.5(M+1).

Example 4.16 Synthesis of1′-methyl-4′-pyrimidin-5-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.14, and makingnon-critical variations using4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (22%) as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ 9.10 (s, 1H), 8.18 (s, 2H), 7.41 (t, 1H), 7.00 (d, 1H),6.85 (d, 1H), 6.20 (s, 1H), 6.12 (s, 1H), 5.87 (d, 2H), 4.54 (ABq, 2H),3.32 (s, 1H); MS (ES+) m/z 374.5 (M+1).

Example 4.17 Synthesis of4′-(3-furyl)-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.14, and makingnon-critical variations using4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 3-furanboronic acid to replace pyrimidine-5-boronic acid, the titlecompound was obtained (81%) as a colorless solid: ¹H NMR (300 MHz,CDCl₃) δ 7.40-7.28 (m, 2H), 7.05-6.95 (m, 1H), 6.90-6.78 (m, 2H),6.45-6.38 (m, 1H), 6.23-6.16 (m, 1H), 6.07-5.97 (m, 1H), 5.97-5.80 (m,2H), 4.75-4.50 (m, 2H), 3.30-3.22 (m, 3H); MS (ES+) m/z 362.4 (M+1).

Example 4.18 Synthesis of4′-(6-fluoropyridin-3-yl)-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.14, and makingnon-critical variations using4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and (6-fluoropyridin-3-yl)boronic acid to replace pyrimidine-5-boronicacid, the title compound was obtained (100%) as a colorless solid: ¹HNMR (300 MHz, CDCl₃) δ 7.75-7.65 (m, 1H), 7.42-7.30 (m, 1H), 7.19-7.05(m, 1H), 7.00-6.90 (m, 1H), 6.90-6.80 (m, 1H), 6.78-6.64 (m, 1H),6.24-6.12 (m, 2H), 5.92-5.79 (m, 2H), 4.74-4.63 (m, 1H), 4.40-4.29 (m,1H), 3.34-3.26 (m, 3H); MS (ES+) m/z 391.4 (M+1).

Example 4.19 Synthesis of1′-(2-cyclopropylethyl)-4′-quinolin-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using4′-bromo-1′-(2-cyclopropylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and quinolin-3-ylboronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained: MS (ES+) m/z 477.5 (M+1)

Example 4.20 Synthesis ofN-(2-fluorophenyl)-2-(2′-oxo-4′-pyrimidin-5-yl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 4, and makingnon-critical variations using2-(4′-bromo-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamideto replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and pyrimidine-5-boronic acid to replace[6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound wasobtained (53%) as a colorless solid: mp 229-230° C.; ¹H NMR (300 MHz,CDCl₃) δ 9.10 (s, 1H), 8.26-8.15 (m, 3H), 7.98 (s, 1H), 7.41 (t, 1H),7.15-7.05 (m, 4H), 6.89 (d, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 4.81-4.76(m, 2H), 4.59-4.42 (m, 4H), 3.00 (t, 2H); ¹³C NMR (75 MHz, CDCl₃) δ178.2, 164.4, 162.5, 161.0, 157.0, 155.8, 141.8, 132.6, 131.1, 129.4,125.8, 125.5, 125.4, 125.2, 125.1, 124.7, 121.9, 120.6, 119.9, 118.7,115.1, 114.8, 109.5, 93.4, 79.0, 72.4, 57.8, 44.9, 28.9; MS (ES+) m/z509.5 (M+1).

Example 5 Synthesis of4′-[(6-methoxypyridin-3-yl)amino]-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To an oven-dried 2-neck 25 mL round bottom flask equipped with acondenser was charged with4′-bromo-1′-pentylspiro-(6,7-dihydrofuro-[2,3-f][1,3]benzodioxole-7,3′-indole)-2′-(1′H)-one(50.5 mg, 0.12 mmol), 5-amino-2-methoxypyridine (22.3 mg, 0.18 mmol),Pd₂(dba)₃ (10 mole %), BINAP (10 mole %) and sodium methoxide (12.9 mg,0.24 mmol). The flask was flushed with nitrogen for 5 min followed bythe addition of degassed toluene (5.00 mL). The reaction mixture washeated at reflux for 16 h. After cooling to ambient temperature, thereaction mixture was diluted with ethyl acetate (20.0 mL) and washedwith saturated ammonium chloride (10.0 mL), brine (10.0 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The brown residue was subjected to columnchromatography eluting with ethyl acetate-hexane (20% to 50%) to yieldthe title compound (30.0 mg) in 54% yield: MS (ES+), m/z 474.3 (M+1).

Example 5.1

The compounds listed in the following table were synthesized usingsimilar conditions as described in EXAMPLE 5. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound MS (m/z, Number Name M + 1) 1984′-[(3,5-difluorophenyl)amino]-1′- 479.1pentylspiro[furo[2,3-f][1,3]benzodioxole- 7,3′-indol]-2′(1′H)-one 1994′-[(4,6-dimethylpyridin-2-yl)amino]-1′- 473.3pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- (M + 2)indol]-2′(1′H)-one 200 4′-[(4-methyl-1,3-thiazol-2-yl)amino]-1′- 464.1pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one

Example 5.2 Synthesis of4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.05 g, 0.12 mmol), 3-(trifluoromethyl)aniline (0.03 g, 0.17 mmol),Pd₂(dba)₃ (0.02 g, 0.01 mmol), xanthphos (0.007 g, 0.01 mmol), andsodium tert-butoxide (0.02 g, 0.17 mmol) in toluene (5.00 mL) was heatedat 110° C. for 4 days. After cooling down to ambient temperature, themixture was extracted with ethyl acetate. The organic phase was driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography eluting with ethyl acetate/hexane to give the titlecompound (0.06 g, 71%) as a solid: MS (ES+) m/z 511.5 (M+1).

Example 5.3

The compounds listed in the following table were synthesized usingsimilar conditions as described in EXAMPLE 5.2. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound MS Number Name (m/z, M + 1) 2014′-morpholino-1′-pentyl-6H-spiro[benzofuro[6,5- 437.5d][1,3]dioxole-7,3′-indolin]-2′-one 2024′-(4-methylpiperazin-1-yl)-1′-pentyl-6H-spiro[benzofuro[6,5- 450.5d][1,3]dioxole-7,3′-indolin]-2′-one 2031′-pentyl-4′-(pyrimidin-4-ylamino)-6H-spiro[benzofuro[6,5- 445.5d][1,3]dioxole-7,3′-indolin]-2′-one 2041′-pentyl-4′-(pyridin-3-ylamino)-6H-spiro[benzofuro[6,5- 444.5d][1,3]dioxole-7,3′-indolin]-2′-one 2054′-(4-chloro-2-(trifluoromethyl)phenylamino)-1′-pentyl-6H- 545.5spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one 2061′-pentyl-4′-(pyrimidin-2-ylamino)-6H-spiro[benzofuro[6,5- 444.5d][1,3]dioxole-7,3′-indolin]-2′-one 2074′-(benzo[d][1,3]dioxol-5-ylamino)-1′-pentyl-6H- 487.5spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one 2084′-(3-fluorophenylamino)-1′-pentyl-6H-spiro[benzofuro[6,5- 461.5d][1,3]dioxole-7,3′-indolin]-2′-one 2094′-(naphthalen-2-ylamino)-1′-pentyl-6H-spiro[benzofuro[6,5- 493.5d][1,3]dioxole-7,3′-indolin]-2′-one 2104′-(2-methoxyphenylamino)-1′-pentyl-6H- 473.2spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one 2114′-(4-methylthiazol-2-ylamino)-1′-pentyl-6H- 464.1spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one 2124′-(4,6-dimethylpyridin-2-ylamino)-1′-pentyl-6H- 473.3spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one 2134′-(3,5-difluorophenylamino)-1′-pentyl-6H- 479.1spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one 2144′-(6-methoxypyridin-3-ylamino)-1′-pentyl-6H- 474.3spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one

Example 6 Synthesis of2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

To a solution of methyl2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1(2′H)-yl)methyl]benzoate(7.56 g, 17.6 mmol) in a mixture of THF/water (2/1 v/v, 180 mL) wasadded lithium hydroxide monohydrate (1.48 g, 35.2 mmol). The resultingmixture was stirred at ambient temperature overnight and concentrated invacuo followed by the addition of water (150 mL). The mixture wasextracted with of ethyl acetate/hexanes, 1/3 v/v, 50.0 mL). The waterlayer was acidified with 1 N HCl solution until the pH value reached 2.The precipitate was filtered and dried to give the title compound (7.30g, 100%) as a white solid: mp>250° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 13.25(s, 1H), 7.95 (dd, 1H), 7.49 (dt, 1H), 7.37 (t, 1H), 7.24-7.16 (m, 2H),7.11-6.98 (m, 2H), 6.80 (d, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 5.91 (s,2H), 5.37-5.19 (m, 2H), 4.88-4.68 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.6, 168.8, 156.0, 148.8, 143.0, 142.3, 137.6, 133.1, 132.1, 131.5,129.9, 129.4, 127.7, 126.5, 124.2, 123.6, 120.1, 109.8, 103.8, 101.9,93.8, 80.5, 58.0, 42.6.

Example 7 Synthesis ofN-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

A. Preparation of Stock Solution of2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoylchloride

A solution of2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (0.21 g, 0.50 mmol), oxalyl chloride (0.09 mL, 1.00 mmol) and onedrop of DMF in toluene (10.0 mL) was stirred at ambient temperatureovernight. The mixture was concentrated under vacuum to afford a solid,which was dissolved in dichloromethane (5.00 mL) to form an acidchloride stock solution (0.10 mmol/mL) for use.

B. Synthesis ofN-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

The acid chloride stock solution obtained above (1.00 mL, 0.10 mmol) wasadded to a mixture of 2-(4-chlorophenyl)ethylamine (0.02 g, 0.13 mmol),triethylamine (0.14 mL, 1.00 mmol) in dichloromethane (1.00 mL). Theresulting mixture was stirred at ambient temperature overnight anddiluted with dichloromethane (5.00 mL). The mixture was washed with 1 NHCl, saturated sodium bicarbonate solution, dried over sodium sulfateand filtered. The filtrate was concentrated under vacuum to dryness togive the title compound as a white powder: ¹H NMR (300 MHz, CDCl₃) δ7.70-7.13 (m, 10H), 7.10-6.96 (m, 2H), 6.65-6.54 (br, 1H), 6.50 (s, 1H),6.11 (s, 1H), 5.89-5.82 (m, 2H), 5.09-4.88 (m, 3H), 4.68 (d, 1H),3.79-3.66 (m, 2H), 2.93 (t, 2H); MS (ES+), m/z 553.3 (M+1), 575.3(M+23).

Example 7.1

The compounds listed in the following table were synthesized usingsimilar conditions as described in EXAMPLE 7. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound MS Number Name (m/z, M + 1) 215N-(3-methylbutyl)-2-[(2′-oxospiro[furo[2,3- 485.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2162-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 491.21′(2′H)-yl)methyl]-N-phenylbenzamide 217N,N-diisopropyl-2-[(2′-oxospiro[furo[2,3- 499.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 218N-(3-fluorophenyl)-2-[(2′-oxospiro[furo[2,3- 509.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 219N-(4-chlorobenzyl)-2-[(2′-oxospiro[furo[2,3- 539.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 220N-butyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 471.3indol]-1′(2′H)-yl)methyl]benzamide 2212-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 485.31′(2′H)-yl)methyl]-N-pentylbenzamide 222N-hexyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 499.4indol]-1′(2′H)-yl)methyl]benzamide 2232-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 457.31′(2′H)-yl)methyl]-N-propylbenzamide 224N-isopropyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 457.37,3′-indol]-1′(2′H)-yl)methyl]benzamide 225N-cyclohexyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 497.37,3′-indol]-1′(2′H)-yl)methyl]benzamide 226N-cyclopentyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 483.37,3′-indol]-1′(2′H)-yl)methyl]benzamide 227N-heptyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 513.4indol]-1′(2′H)-yl)methyl]benzamide 228N-(4-fluorophenyl)-2-[(2′-oxospiro[furo[2,3- 509.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 229N-(3-fluorobenzyl)-2-[(2′-oxospiro[furo[2,3- 523.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 230N-(3-chlorophenyl)-2-[(2′-oxospiro[furo[2,3- 525.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 231N-(2-fluorophenyl)-2-[(2′-oxospiro[furo[2,3- 509.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 232N-(2-ethylphenyl)-2-[(2′-oxospiro[furo[2,3- 519.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 233N-(4-ethylphenyl)-2-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 234N-(3-methylphenyl)-2-[(2′-oxospiro[furo[2,3- 505.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 235N-(2,3-dimethylphenyl)-2-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 236N-(3,5-dimethylphenyl)-2-[(2′-oxospiro[furo[2,3- 519.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2371′-[2-(piperidin-1-ylcarbonyl)benzyl]spiro[furo[2,3- 483.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 238N-isobutyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 471.2indol]-1′(2′H)-yl)methyl]benzamide 239N-(2-chlorobenzyl)-2-[(2′-oxospiro[furo[2,3- 539.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 240N-(2,6-dimethylphenyl)-2-[(2′-oxospiro[furo[2,3- 519.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 241N-(2-methoxyphenyl)-2-[(2′-oxospiro[furo[2,3- 521.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 242N-(3-methoxypropyl)-2-[(2′-oxospiro[furo[2,3- 487.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 243N-[2-(4-methylphenyl)ethyl]-2-[(2′-oxospiro[furo[2,3- 533.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2442-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 499.21′(2′H)-yl)methyl]-N-(tetrahydrofuran-2- ylmethyl)benzamide 245N,N-dibenzyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 595.27,3′-indol]-1′(2′H)-yl)methyl]benzamide 2462-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 533.21′(2′H)-yl)methyl]-N-(3-phenylpropyl)benzamide 247N-[2-(3-chlorophenyl)ethyl]-2-[(2′-oxospiro[furo[2,3- 553.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 248N-[2-(4-fluorophenyl)ethyl]-2-[(2′-oxospiro[furo[2,3- 537.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 249N-(4-fluorobenzyl)-2-[(2′-oxospiro[furo[2,3- 523.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 250N-(3-ethoxypropyl)-2-[(2′-oxospiro[furo[2,3- 501.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 251N-hexyl-N-methyl-2-[(2′-oxospiro[furo[2,3- 513.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 252N-(3-isopropoxypropyl)-2-[(2′-oxospiro[furo[2,3- 515.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 253N-(4-methoxybenzyl)-2-[(2′-oxospiro[furo[2,3- 535.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 254N-(cyclopropylmethyl)-2-[(2′-oxospiro[furo[2,3- 469.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 255N-(2-ethoxyethyl)-2-[(2′-oxospiro[furo[2,3- 487.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 256N-(cyclohexylmethyl)-2-[(2′-oxospiro[furo[2,3- 511.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 257N-(2-furylmethyl)-2-[(2′-oxospiro[furo[2,3- 495.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 258N-(2,4-dimethylphenyl)-2-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 259N-(4-cyanophenyl)-2-[(2′-oxospiro[furo[2,3- 516.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 260N-(3,5-dichlorophenyl)-2-[(2′-oxospiro[furo[2,3- 559.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 261N-(3-fluoro-2-methylphenyl)-2-[(2′-oxospiro[furo[2,3- 523.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 262N-(4-methoxyphenyl)-2-[(2′-oxospiro[furo[2,3- 521.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 263N-(5-chloro-2-methylphenyl)-2-[(2′-oxospiro[furo[2,3- 539.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2642-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 559.11′(2′H)-yl)methyl]-N-[3- (trifluoromethyl)phenyl]benzamide 2652-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 506.11′(2′H)-yl)methyl]-N-(pyridin-4-ylmethyl)benzamide 266N-cyclobutyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 469.17,3′-indol]-1′(2′H)-yl)methyl]benzamide 267N-methyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 429.1indol]-1′(2′H)-yl)methyl]benzamide 268N-ethyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 443.1indol]-1′(2′H)-yl)methyl]benzamide 2692-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 497.11′(2′H)-yl)methyl]-N-(2,2,2-trifluoroethyl)benzamide 270N-(2,2-diphenylethyl)-2-[(2′-oxospiro[furo[2,3- 595.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 271N-[2-(diethylamino)ethyl]-2-[(2′-oxospiro[furo[2,3- 514.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 272N-(3,3-dimethylbutyl)-2-[(2′-oxospiro[furo[2,3- 499.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 273N-(2-ethylbutyl)-2-[(2′-oxospiro[furo[2,3- 499.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2742-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 512.41′(2′H)-yl)methyl]-N-(2-pyrrolidin-1-ylethyl)benzamide 275N-[(1-ethylpyrrolidin-2-yl)methyl]-2-[(2′-oxospiro[furo[2,3- 526.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2762-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 526.51′(2′H)-yl)methyl]-N-(2-piperidin-1-ylethyl)benzamide 277N-(2-morpholin-4-ylethyl)-2-[(2′-oxospiro[furo[2,3- 528.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 278N-[(1S)-1-cyclohexylethyl]-2-[(2′-oxospiro[furo[2,3- 525.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 279N-(2-fluoro-5-methylphenyl)-2-[(2′-oxospiro[furo[2,3- 523.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 280N-(2,4-difluorophenyl)-2-[(2′-oxospiro[furo[2,3- 527.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2812-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 533.41′(2′H)-yl)methyl]-N-(4-propylphenyl)benzamide 282N-(3,3-diphenylpropyl)-2-[(2′-oxospiro[furo[2,3- 609.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 283N-(2-methoxyethyl)-2-[(2′-oxospiro[furo[2,3- 473.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 284N-(2,5-difluorobenzyl)-2-[(2′-oxospiro[furo[2,3- 541.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2852-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 511.41′(2′H)-yl)methyl]-N-(2-thienylmethyl)benzamide 286N-[4-chloro-2-(trifluoromethyl)phenyl]-2-[(2′- 593.3oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 287N-[2-(4-methoxyphenyl)ethyl]-2-[(2′-oxospiro[furo[2,3- 549.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 288N-(3,5-dichlorobenzyl)-2-[(2′-oxospiro[furo[2,3- 573.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 289N-(3-chlorobenzyl)-2-[(2′-oxospiro[furo[2,3- 539.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2902-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 525.41′(2′H)-yl)methyl]-N-[2-(2-thienyl)ethyl]benzamide 291N-(2,3-dihydro-1H-inden-1-yl)-2-[(2′-oxospiro[furo[2,3- 531.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2922-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 573.31′(2′H)-yl)methyl]-N-[4- (trifluoromethyl)benzyl]benzamide 293N-[4-fluoro-2-(trifluoromethyl)phenyl]-2-[(2′- 577.5oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 2942-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 506.41′(2′H)-yl)methyl]-N-(pyridin-3-ylmethyl)benzamide 2952-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 573.31′(2′H)-yl)methyl]-N-[2- (trifluoromethyl)benzyl]benzamide 296N-(3-methylpyridin-2-yl)-2-[(2′-oxospiro[furo[2,3- 506.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 297N-(1-benzylpiperidin-4-yl)-2-[(2′-oxospiro[furo[2,3- 588.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 2982-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 559.41′(2′H)-yl)methyl]-N-[2- (trifluoromethyl)phenyl]benzamide 299N-[(1R)-1-cyclohexylethyl]-2-[(2′-oxospiro[furo[2,3- 525.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 300N-(2-cyanoethyl)-2-[(2′-oxospiro[furo[2,3- 468.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 301N-(6-methoxypyridin-3-yl)-2-[(2′-oxospiro[furo[2,3- 522.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3022-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 498.31′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide 3032-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 499.31′(2′H)-yl)methyl]-N-1,3,4-thiadiazol-2-ylbenzamide 304N-(4,6-dimethylpyridin-2-yl)-2-[(2′-oxospiro[furo[2,3- 520.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 305N-(2,3-dihydro-1H-inden-5-yl)-2-[(2′-oxospiro[furo[2,3- 531.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3061′-{2-[(4-pyrimidin-2-ylpiperazin-1- 562.4yl)carbonyl]benzyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 3071′-(2-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1- 618.4yl]carbonyl}benzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 308N-2-adamantyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 549.57,3′-indol]-1′(2′H)-yl)methyl]benzamide 309N-1-adamantyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 549.57,3′-indol]-1′(2′H)-yl)methyl]benzamide 310N-1-naphthyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 541.47,3′-indol]-1′(2′H)-yl)methyl]benzamide 311N-(3,5-difluorophenyl)-2-[(2′-oxospiro[furo[2,3- 527.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3121′-[2-(morpholin-4-ylcarbonyl)benzyl]spiro[furo[2,3- 485.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 313N-[3-(dimethylamino)propyl]-N-methyl-2-[(2′- 514.4oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

Example 8 Synthesis of3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

Following the procedure described in EXAMPLE 6, and making non-criticalvariations using methyl3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoateto replace methyl2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1(2′H)-yl)methyl]benzoate,the title compound was obtained (100%): ¹H NMR (300 MHz, CDCl₃) δ 13.03(s, 1H), 7.86-7.80 (m, 2H), 7.59-7.57 (m, 1H), 7.48-7.44 (m, 1H),7.25-7.16 (m, 2H), 7.03-6.95 (m, 2H), 6.68 (s, 1H), 6.18 (s, 1H), 5.90(s, 2H), 5.05 (ABq, 2H), 4.75 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.4, 167.5, 155.9, 148.9, 142.5, 142.3, 137.3, 132.2, 131.7, 129.6,129.4, 128.8, 128.1, 124.3, 123.7, 120.1, 109.9, 103.3, 101.9, 93.9,80.3, 58.0, 43.2; MS (ES+) m/z 416.2 (M+1).

Example 9 Synthesis ofN-[2-(3-chlorophenyl)ethyl]-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

A. Preparation of stock solution of3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoyl chloride

To a stirred slurry of3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (2.08 g, 5.00 mmol) in dry chloroform (50.0 mL) was added oxalylchloride (0.95 g, 7.5 mmol) at ambient temperature followed by 1 drop ofDMF. The mixture was stirred at ambient temperature overnight andevaporated to dryness in vacuo. The residue was dissolved in drydichlormethane (60.0 mL) to form an acid chloride stock solution foruse.

B. Synthesis ofN-[2-(3-Chlorophenyl)ethyl]-3-[2′-oxospiro[furo[(2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

To a solution of 2-(3-chlorophenyl)ethylamine (0.02 mL, 0.24 mmol) indry dichloromethane (2.00 mL) and triethylamine (0.05 mL, 0.32 mmol) wasadded the acid chloride stock solution (2.0 mL, 0.081 M indichloromethane) obtained above at ambient temperature. The mixture wasstirred for 2 h, washed with 15% HCl solution and water. The organiclayer was separated, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was dissolved in ethylacetate, and the product was precipitated by the addition of hexane. Thewhite solid was filtered and collected to yield the title compound (0.06g) in 65% yield: ¹H NMR (300 MHz, CDCl₃) δ 7.97-7.95 (m, 2H), 7.53-7.50(m, 1H), 7.45-7.40 (m, 1H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H),6.73-6.71 (m, 1H), 6.52 (s, 1H), 6.20 (s, 1H), 5.86 (s, 1H), 5.18 (d,1H), 4.72 (d, 1H), 4.80 (d, 1H), 4.69 (d, 1H), 3.89 (s, 1H); MS (ES+)m/z 554.0 (M+1).

Example 9.1

The compounds listed in the following table were synthesized using thesimilar procedure as described in EXAMPLE 9. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound Number Name MS (m/z, M + 1) 314N-(3-methylbutyl)-3-[(2′-oxospiro[furo[2,3- 485.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3153-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 491.51′(2′H)-yl)methyl]-N-phenylbenzamide 316N,N-diisopropyl-3-[(2′-oxospiro[furo[2,3- 499.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 317N-(3-fluorophenyl)-3-[(2′-oxospiro[furo[2,3- 509.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 318N-(4-chlorobenzyl)-3-[(2′-oxospiro[furo[2,3- 540.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 319N-butyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 471.5indol]-1′(2′H)-yl)methyl]benzamide 320N-(3-fluorobenzyl)-3-[(2′-oxospiro[furo[2,3- 523.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 321N-(3-chlorophenyl)-3-[(2′-oxospiro[furo[2,3- 526.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 322N-(2-fluorophenyl)-3-[(2′-oxospiro[furo[2,3- 509.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 323N-(2-ethylphenyl)-3-[(2′-oxospiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 324N-(4-ethylphenyl)-3-[(2′-oxospiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 325N-(3-methylphenyl)-3-[(2′-oxospiro[furo[2,3- 505.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 326N-(2,3-dimethylphenyl)-3-[(2′-oxospiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 327N-(3,5-dimethylphenyl)-3-[(2′-oxospiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3283-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 485.51′(2′H)-yl)methyl]-N-pentylbenzamide 3293-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 457.51′(2′H)-yl)methyl]-N-propylbenzamide 330N-isopropyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 457.57,3′-indol]-1′(2′H)-yl)methyl]benzamide 3311′-[3-(piperidin-1-ylcarbonyl)benzyl]spiro[furo[2,3- 483.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 332N-isobutyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 471.57,3′-indol]-1′(2′H)-yl)methyl]benzamide 333N-hexyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 499.67,3′-indol]-1′(2′H)-yl)methyl]benzamide 334N-cyclohexyl-3-[(2′-oxospiro[furo[2,3- 497.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 335N-cyclopentyl-3-[(2′-oxospiro[furo[2,3- 483.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 336N-heptyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 513.67,3′-indol]-1′(2′H)-yl)methyl]benzamide 337N-(2-methoxybenzyl)-3-[(2′-oxospiro[furo[2,3- 535.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 338N-(2-methoxyphenyl)-3-[(2′-oxospiro[furo[2,3- 521.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 339N-cyclopropyl-3-[(2′-oxospiro[furo[2,3- 455.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 340N-(3-methoxypropyl)-3-[(2′-oxospiro[furo[2,3- 487.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 341N-(2,4-dimethylphenyl)-3-[(2′-oxospiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3423-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 499.51′(2′H)-yl)methyl]-N-(tetrahydrofuran-2- ylmethyl)benzamide 343N,N-dibenzyl-3-[(2′-oxospiro[furo[2,3- 595.7f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 344N-[2-(diethylamino)ethyl]-3-[(2′-oxospiro[furo[2,3- 514.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 345N-methyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 429.47,3′-indol]-1′(2′H)-yl)methyl]benzamide 3463-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 559.51′(2′H)-yl)methyl]-N-[3- (trifluoromethyl)phenyl]benzamide 347N-ethyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 443.5indol]-1′(2′H)-yl)methyl]benzamide 348N-(3-ethoxypropyl)-3-[(2′-oxospiro[furo[2,3- 501.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 349N-(4-methoxybenzyl)-3-[(2′-oxospiro[furo[2,3- 535.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 350N-(3,5-dichlorophenyl)-3-[(2′-oxospiro[furo[2,3- 560.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3513-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 492.51′(2′H)-yl)methyl]-N-pyridin-3-ylbenzamide 3523-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 506.51′(2′H)-yl)methyl]-N-(pyridin-4-ylmethyl)benzamide 353N-(2-furylmethyl)-3-[(2′-oxospiro[furo[2,3- 495.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 354N-(3-fluoro-2-methylphenyl)-3-[(2′-oxospiro[furo[2,3- 523.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 355N-hexyl-N-methyl-3-[(2′-oxospiro[furo[2,3- 513.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 356N-(3-isopropoxypropyl)-3-[(2′-oxospiro[furo[2,3- 515.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 357N-(2-ethoxyethyl)-3-[(2′-oxospiro[furo[2,3- 487.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 358N-(cyclopropylmethyl)-3-[(2′-oxospiro[furo[2,3- 469.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 359N-(4-methoxyphenyl)-3-[(2′-oxospiro[furo[2,3- 521.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 360N-cyclobutyl-3-[(2′-oxospiro[furo[2,3- 469.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 361N-[2-(4-fluorophenyl)ethyl]-3-[(2′-oxospiro[furo[2,3- 537.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 362N-(cyclohexylmethyl)-3-[(2′-oxospiro[furo[2,3- 511.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 363N-[2-(4-methylphenyl)ethyl]-3-[(2′-oxospiro[furo[2,3- 533.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 364N-(2-ethylbutyl)-3-[(2′-oxospiro[furo[2,3- 499.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 365N-benzyl-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 505.57,3′-indol]-1′(2′H)-yl)methyl]benzamide 366N-(2-methoxyethyl)-3-[(2′-oxospiro[furo[2,3- 473.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3671′-[3-(morpholin-4-ylcarbonyl)benzyl]spiro[furo[2,3- 485.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 368N-(1-benzylpiperidin-4-yl)-3-[(2′-oxospiro[furo[2,3- 588.7f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 369N-[2-(4-methoxyphenyl)ethyl]-3-[(2′-oxospiro[furo[2,3- 549.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3703-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 526.61′(2′H)-yl)methyl]-N-(2-piperidin-1- ylethyl)benzamide 371N-(1-cyclohexylethyl)-3-[(2′-oxospiro[furo[2,3- 525.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3723-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 511.61′(2′H)-yl)methyl]-N-(2-thienylmethyl)benzamide 3733-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 533.61′(2′H)-yl)methyl]-N-(4-propylphenyl)benzamide 374N-(2,4-difluorobenzyl)-3-[(2′-oxospiro[furo[2,3- 541.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 375N-(3,5-difluorophenyl)-3-[(2′-oxospiro[furo[2,3- 527.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 376N-(2,3-dihydro-1H-inden-5-yl)-3-[(2′-oxospiro[furo[2,3- 531.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3773-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 573.51′(2′H)-yl)methyl]-N-[4- (trifluoromethyl)benzyl]benzamide 3783-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 525.61′(2′H)-yl)methyl]-N-[2-(2-thienyl)ethyl]benzamide 3793-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 506.51′(2′H)-yl)methyl]-N-(pyridin-3-ylmethyl)benzamide 3803-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 573.51′(2′H)-yl)methyl]-N-[2- (trifluoromethyl)benzyl]benzamide 381N-[2-(4-chlorophenyl)ethyl]-3-[(2′-oxospiro[furo[2,3- 554.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3823-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 512.61′(2′H)-yl)methyl]-N-(2-pyrrolidin-1- ylethyl)benzamide 383N-(3-methylpyridin-2-yl)-3-[(2′-oxospiro[furo[2,3- 506.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 384N-1,3-benzodioxol-5-yl-3-[(2′-oxospiro[furo[2,3- 535.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 385N-(2-morpholin-4-ylethyl)-3-[(2′-oxospiro[furo[2,3- 528.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3861′-{3-[(4-pyrimidin-2-ylpiperazin-1- 562.6yl)carbonyl]benzyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 3873-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 498.51′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide 388N-(6-methoxypyridin-3-yl)-3-[(2′-oxospiro[furo[2,3- 522.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 389N-(3,5-dichlorobenzyl)-3-[(2′-oxospiro[furo[2,3- 574.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 390N-1-naphthyl-3-[(2′-oxospiro[furo[2,3- 541.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 391N-(4,6-dimethylpyridin-2-yl)-3-[(2′-oxospiro[furo[2,3- 520.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3923-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 493.51′(2′H)-yl)methyl]-N-pyrimidin-4-ylbenzamide 393N-(5-methyl-1,3-thiazol-2-yl)-3-[(2′-oxospiro[furo[2,3- 512.5f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 394N-(4-methylbenzyl)-3-[(2′-oxospiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 395N-[3-(1H-imidazol-1-yl)propyl]-3-[(2′-oxospiro[furo[2,3- 523.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 3961′-{3-[(4-methylpiperazin-1- 498.5 yl)carbonyl]benzyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 397N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-[(2′- 539.6oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 3983-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 499.51′(2′H)-yl)methyl]-N-1,3,4-thiadiazol-2- ylbenzamide 399N-(3,3-dimethylbutyl)-3-[(2′-oxospiro[furo[2,3- 499.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 400N-(4-morpholin-4-ylphenyl)-3-[(2′-oxospiro[furo[2,3- 576.6f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 401N-[(1-ethylpyrrolidin-2-yl)methyl]-3-[(2′- 526.6oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 402N-(2-cyanoethyl)-3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 403N-(2,2-diphenylethyl)-3-[(2′-oxospiro[furo[2,3- 595.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide

Example 10 Synthesis of1′-(4-fluorobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.16 g, 0.57mmol) in ethylmethylketone (5.00 mL) was added Cs₂CO₃ (0.40 g, 1.20mmol). The reaction mixture was stirred at ambient temperature for 15min followed by the addition of 4-fluorobenzyl bromide (0.20 g, 1.0mmol). The reaction mixture was refluxed for 4 h. After the completionof the reaction, the mixture was filtered and the solvent was removedunder reduced pressure. The residue was recrystallized from EtOAc/Hexaneto yield the title compound (0.111 g) as a white solid in 50% yield: MS(ES+) m/z 390.3 (M+1).

Example 10.1

The compounds listed in the following table were synthesized using thesimilar procedure as described in EXAMPLE 10. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound Number Name MS (m/z, M + 1) 4041′-{[1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4- 489.3yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one405 1′-prop-2-yn-1-ylspiro[furo[2,3-f][1,3]benzodioxole- 320.37,3′-indol]-2′(1′H)-one 4061′-benzylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- 372.2indol]-2′(1′H)-one 407 1′-{[6-(trifluoromethyl)pyridin-3- 441.2yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one408 1′-(3,5-difluorobenzyl)spiro[furo[2,3- 408.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4091′-(3-nitrobenzyl)spiro[furo[2,3-f][1,3]benzodioxole- 417.27,3′-indol]-2′(1′H)-one 4101′-[(6-chloropyridin-3-yl)methyl]spiro[furo[2,3- 407.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4111′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[furo[2,3- 380.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4121′-(3-fluorobenzyl)spiro[furo[2,3-f][1,3]benzodioxole- 390.37,3′-indol]-2′(1′H)-one 4131′-(tetrahydrofuran-2-ylmethyl)spiro[furo[2,3- 365.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4143-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 397.2indol]-1′(2′H)-yl)methyl]benzonitrile 4151′-(2,3-dihydro-1,4-benzodioxin-2- 430.3ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 4161′-(2-ethoxyethyl)spiro[furo[2,3-f][1,3]benzodioxole- 354.27,3′-indol]-2′(1′H)-one 417 1′-[(2E)-pent-2-en-1-yl]spiro[furo[2,3-350.2 f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4181′-hex-5-en-1-ylspiro[furo[2,3-f][1,3]benzodioxole- 364.37,3′-indol]-2′(1′H)-one 419 1′-(cyclobutylmethyl)spiro[furo[2,3- 350.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4201′-pent-2-yn-1-ylspiro[furo[2,3-f][1,3]benzodioxole- 348.27,3′-indol]-2′(1′H)-one 4211′-(5-chloropentyl)spiro[furo[2,3-f][1,3]benzodioxole- 386.27,3′-indol]-2′(1′H)-one 4221′-[4-(1H-pyrazol-1-yl)benzyl]spiro[furo[2,3- 438.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4231′-[(7-methoxy-2-oxo-2H-1,4-benzoxazin-3- 471.3yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one424 1′-(4-fluorobutyl)spiro[furo[2,3-f][1,3]benzodioxole- 356.27,3′-indol]-2′(1′H)-one 4251′-(5-methylhexyl)spiro[furo[2,3-f][1,3]benzodioxole- 380.37,3′-indol]-2′(1′H)-one 4261′-[(3Z)-4-methylhex-3-en-1-yl]spiro[furo[2,3- 378.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4271′-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4- 453.2yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one428 1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3- 430.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4291′-(3,4-dihydro-2H-1,5-benzodioxepin-7- 444.3ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 4301′-(biphenyl-4-ylmethyl)spiro[furo[2,3- 448.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4314′-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 473.3indol]-1′(2′H)-yl)methyl]biphenyl-2-carbonitrile 4321′-(2-bromoethyl)spiro[furo[2,3-f][1,3]benzodioxole- 389.17,3′-indol]-2′(1′H)-one 4331′-(1H-1,2,3-triazol-4-ylmethyl)spiro[furo[2,3- 363.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4341′-(biphenyl-2-ylmethyl)spiro[furo[2,3- 448.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4351′-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole- 448.37,3′-indol]-2′(1′H)-one 4365-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 363.2indol]-1′(2′H)-yl)pentanenitrile 4371′-[2-(2-methoxyethoxy)ethyl]spiro[furo[2,3- 384.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4381′-(cyclopropylmethyl)spiro[furo[2,3- 336.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4391′-(4,4,4-trifluorobutyl)spiro[furo[2,3- 392.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 440 ethyl1-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 449.37,3′-indol]-1′(2′H)-yl)ethyl]-1H-1,2,3-triazole-5- carboxylate 441 ethyl1-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 449.37,3′-indol]-1′(2′H)-yl)ethyl]-1H-1,2,3-triazole-4- carboxylate 442diethyl [2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 446.17,3′-indol]-1′(2′H)-yl)ethyl]phosphonate 4431′-(1,3-thiazol-4-ylmethyl)spiro[furo[2,3- 379.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4441′-[(5-chloro-1-benzothien-3-yl)methyl]spiro[furo[2,3- 462.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4451′-(pyridin-2-ylmethyl)spiro[furo[2,3- 373.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4461′-(pyridin-4-ylmethyl)spiro[furo[2,3- 373.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4471′-(pyridin-3-ylmethyl)spiro[furo[2,3- 373.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4481′-[2-(1H-pyrrol-1-yl)ethyl]spiro[furo[2,3- 375.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4491′-{[4-chloro-2-(trifluoromethyl)quinolin-6- 525.1yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one450 1′-(4-fluoro-3-methylbenzyl)spiro[furo[2,3- 404.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4511′-(5-fluoro-2-methylbenzyl)spiro[furo[2,3- 404.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4521′-[(2-methyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3- 393.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4531′-(1,3-benzothiazol-2-ylmethyl)spiro[furo[2,3- 329.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4541′-(2,5-difluorobenzyl)spiro[furo[2,3- 408.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4551′-[4-(1H-pyrrol-1-yl)benzyl]spiro[furo[2,3- 437.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4561′-[3-(1H-pyrrol-1-yl)benzyl]spiro[furo[2,3- 437.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4571′-(2,1,3-benzothiadiazol-4-ylmethyl)spiro[furo[2,3- 430.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4581′-(2,1,3-benzothiadiazol-5-ylmethyl)spiro[furo[2,3- 430.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4591′-[(1-methyl-1H-1,2,3-benzotriazol-5- 427.2yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one460 1′-[(4-chlorophenoxy)methyl]spiro[furo[2,3- 422.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4611′-[2-fluoro-3-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4621′-[2-fluoro-6-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4631′-[3-fluoro-4-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4641′-[4-fluoro-3-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4651′-[2-fluoro-5-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4661′-[4-fluoro-2-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4671′-[5-fluoro-2-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4681′-[2-fluoro-4-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4691′-[3-(1H-pyrrol-1-yl)propyl]spiro[furo[2,3- 389.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 470 1′-[(2,2,3,3- 422.1tetrafluorocyclobutyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4711′-[(3-methyl-5-phenylisoxazol-4- 453.3yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one472 1′-[2-(diethylamino)ethyl]spiro[furo[2,3- 381.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4731′-(2,3-difluorobenzyl)spiro[furo[2,3- 408.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4741′-[(1-bromo-2-naphthyl)methyl]spiro[furo[2,3- 501.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4751′-[(7-methoxy-2-oxo-2H-chromen-4- 470.3yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one476 1′-[(benzyloxy)methyl]spiro[furo[2,3- 402.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4771′-[2-(2,5,5-trimethyl-1,3-dioxan-2- 438.2yl)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one 4781′-[(6-fluoro-4H-1,3-benzodioxin-8- 448.2yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one479 1′-allylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 322.32′(1′H)-one 480 1′-(1-naphthylmethyl)spiro[furo[2,3- 423.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4811′-[3-fluoro-5-(trifluoromethyl)benzyl]spiro[furo[2,3- 458.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4821′-(2,4-difluorobenzyl)spiro[furo[2,3- 408.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4831′-(2,6-difluorobenzyl)spiro[furo[2,3- 408.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4841′-[(5-phenyl-1,3-oxazol-4-yl)methyl]spiro[furo[2,3- 439.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4851′-(3,5,5-trimethylhexyl)spiro[furo[2,3- 408.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4861′-(2-ethylbutyl)spiro[furo[2,3-f][1,3]benzodioxole- 366.37,3′-indol]-2′(1′H)-one 4871′-(4-methylpentyl)spiro[furo[2,3-f][1,3]benzodioxole- 366.37,3′-indol]-2′(1′H)-one 488 1′-(3-methoxybenzyl)spiro[furo[2,3- 402.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4891′-(3-methylbutyl)spiro[furo[2,3-f][1,3]benzodioxole- 352.27,3′-indol]-2′(1′H)-one 490 1′-(3-methylbut-2-en-1-yl)spiro[furo[2,3-350.2 f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4911′-pent-4-en-1-ylspiro[furo[2,3-f][1,3]benzodioxole- 350.27,3′-indol]-2′(1′H)-one 4924-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 349.1indol]-1′(2′H)-yl)butanenitrile 4931′-[4-(1H-1,2,4-triazol-1-yl)benzyl]spiro[furo[2,3- 439.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4941′-(1,3-benzodioxol-5-ylmethyl)spiro[furo[2,3- 416.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4951′-[4,4-bis(4-fluorophenyl)butyl]spiro[furo[2,3- 526.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4961′-[(2-methylcyclopropyl)methyl]spiro[furo[2,3- 350.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4971′-(3-cyclopropylpropyl)spiro[furo[2,3- 364.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4981′-hexylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 366.32′(1′H)-one 499 1′-[(2-cyclopropyl-6-hydroxypyrimidin-4- 430.3yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one

Example 10.2 Synthesis of1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 10, and makingnon-critical variations using tert-butyl4-(bromomethyl)peridine-1-carboxylate to replace 4-fluorobenzyl bromide,the title compound was obtained in 67% yield as a white solid uponacidification of the intermediate with 33% HBr: MS (ES+) m/z 379.3(M+1).

Example 10.3 Synthesis of1′-[(1-methylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

To a solution of1-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.19 g, 0.50 mmol) in dichloroethane (5.00 mL) was added formaldehyde(0.10 mL, 33% solution, 0.03 g, 1.10 mmol) and sodiumtriacetoxyborohydride (0.30 g, 1.40 mmol). After stirring at ambienttemperature for 20 hours, the reaction mixture was diluted with ofdichloromethane (20.0 mL) and washed with water (2×20.0 mL). The organiclayer was dried over sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography and the product was dissolved in dichloromethane (5.00mL) and excess of HCl in ether was added. The precipitate was filteredto give the title compound in 20% yield: MS (ES+) m/z 393.3 (M+1).

Example 10.4 Synthesis of1′-[(1-ethylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using acetaldehyde to replace formalin, thetitle compound was obtained in 20% yield as a white solid: MS (ES+) m/z407.3 (M+1).

Example 10.5 Synthesis of1′-[(1-cyclohexyllpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using cyclohexanone to replace formalin, thetitle compound was obtained 24% yield as a white solid: MS (ES+) m/z461.5 (M+1).

Example 10.6 Synthesis of1′-{[1-cyclopropylmethyl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using cyclopropanecarbaldehyde to replaceformalin, the title compound was obtained in 14% yield as a white solid:MS (ES+) m/z 433.5 (M+1).

Example 10.7 Synthesis of1-[(1-cyclopentylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using cyclopentanone to replace formalin, thetitle compound was obtained in 37% yield as a white solid: MS (ES+) m/z447.3 (M+1).

Example 10.8 Synthesis of1′-{[1-(pyridine-3-ylmethyl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using nicotinaldehyde to replace formalin, thetitle compound was obtained in 11% yield as a white solid: MS (ES+) m/z470.4 (M+1).

Example 10.9 Synthesis of1′-{[1-(3-methylbutyl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using 3-methylbutanal to replace formalin, thetitle compound was obtained in 15% yield as a white solid: MS (ES+) m/z449.5 (M+1).

Example 10.10 Synthesis of1′-{[1-(1-ethylpropyl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using pentan-3-one to replace formalin, thetitle compound was obtained in 17% yield as a white solid: MS (ES+) m/z449.4 (M+1).

Example 10.11 Synthesis of1′-[(1-cyclobutylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using cyclobutanone to replace formalin, thetitle compound was obtained in 31% yield as a white solid: MS (ES+) m/z433.4 (M+1).

Example 10.12 Synthesis of1′-[(1-isopropyllpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in Example 10.3, and makingnon-critical variations using acetone to replace formalin, the titlecompound was obtained in 31% yield as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 10.36 (s, 1H), 7.79-6.87 (m, 4H), 6.82-6.48 (m, 1H),6.38-6.15 (m, 1H), 5.89 (s, 2H), 4.67 (ABq, 2H), 4.12 (s, 1H), 3.79-0.60(m, 16H); MS (ES+) m/z 421.4 (M+1).

Example 10.13 Synthesis of1′-{[1-(pyridin-2-ylmethyl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using picolinaldehyde to replace formalin, thetitle compound was obtained in 15% yield as a white solid: MS (ES+) m/z470.4 (M+1).

Example 10.14 Synthesis of1′-{[1-(2-thienylmethyl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using thiophene-2-carbaldehyde to replaceformalin, the title compound was obtained in 21% yield as a white solid:MS (ES+) m/z 475.3 (M+1).

Example 10.15 Synthesis of1-({1-[3-(methylthio)propyl]piperidin-4-yl}methyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using 3-(methylthio)propanal to replaceformalin, the title compound was obtained in 7% yield as a white solid:MS (ES+) m/z 467.5 (M+1).

Example 10.16 Synthesis of1′-{[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using tetrahydro-4H-pyran-4-one to replaceformalin, the title compound was obtained in 33% yield as a white solid:MS (ES+) m/z 463.4 (M+1).

Example 10.17 Synthesis of1′-{[1-(3,3-dimethylbutyl)piperidin-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.3, and makingnon-critical variations using 3,3-dimethylbutanal to replace formalin,the title compound was obtained in 19% yield as a white solid: MS (ES+)m/z 463.5 (M+1).

Example 10.18 Synthesis of tert-butyl4-[(5,5-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate

Following the procedure as described in EXAMPLE 10, and makingnon-critical variations using5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace4-fluorobenzyl bromide, the title compound was obtained in 70% yield: mp65-75° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.30 (td, 1H), 7.18 (d, 1H), 7.05(t, 1H), 6.89 (d, 1H), 6.38 (s, 1H), 6.28 (s, 1H), 4.88 (d, 1H), 4.64(d, 1H), 4.18 (s, 2H), 4.17-4.01 (br, 2H), 3.74-3.53 (m, 2H), 2.74-2.59(m, 2H), 2.11-1.92 (m, 1H), 1.70-1.59 (m, 2H), 1.43 (s, 9H), 1.37-1.19(m, 2H), 1.17 (s, 3H), 1.14 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.0,161.3, 161.0, 154.7, 142.8, 132.6, 129.9, 128.7, 124.2, 123.3, 120.3,116.2, 108.5, 93.4, 85.4, 80.6, 79.5, 57.7, 45.7, 41.3, 35.0, 30.0,28.4, 27.8, 27.5; MS (ES+) m/z 527.5 (M+23).

Example 10.19 Synthesis of5,5-dimethyl-1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

To a stirred solution of tert-butyl4-[(5,5-dimethyl-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate(80 mg, 0.16 m mol) in 10.0 mL dichloromethane was added hydrobromicacid (0.50 mL of hydrobromic acid ≧33% in glacial acetic acid, 1.60mmol) slowly at 0° C. The mixture was stirred at ambient temperature forone hour and concentrated in vacuo to dryness. The residue was treatedwith 10.0 mL of 2 N sodium hydroxide solution and extracted withdichloromethane (3×30.0 mL). The combined organic layers was washed withbrine (100 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto column chromatography (2% methanol in ethyl acetate) to give5,5-dimethyl-1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.03 g, 46%), which was treated with 2.0 M HCl in diethyl ether to givethe title compound: ¹H NMR (300 MHz, CD₃OD) δ 7.41 (td, 1H), 7.25-7.12(m, 3H), 6.43 (s, 1H), 6.37 (s, 1H), 4.87 (d, 1H), 4.72 (d, 1H), 4.23(s, 2H), 3.80 (d, 2H), 3.51-3.38 (m, 2H), 3.11-2.94 (m, 2H), 2.39-2.19(m, 1H), 2.06-1.94 (m, 2H), 1.67-1.49 (m, 2H), 1.22 (s, 3H), 1.19 (s,3H); ¹³C NMR (75 MHz, CD₃OD) δ 181.4, 163.9, 163.4, 144.7, 134.7, 132.3,131.0, 125.9, 125.8, 122.6, 118.4, 111.3, 94.9, 87.4, 82.6, 60.2, 46.7,45.7, 45.6, 43.3, 34.6, 28.8, 28.7, 28.6; MS (ES+) m/z 405.4 (M+1).

Example 10.20 Synthesis of7′-fluoro-1′-[(1-isopropylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

A. Following the procedure as described in EXAMPLES 10.18 and 10.19, andmaking non-critical variations using7′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained and used in the next step.

B. To a stirred solution of7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(120 mg, 0.28 mmol) and triethylamine (3.9 μL, 0.028 mmol) in 5.00 mLdichloromethane was added acetone (4.1 μL, 0.56 mmol) followed withsodium triacetoxyborohydride (124 mg, 0.56 mmol) at ambient temperature.The mixture was stirred at ambient temperature overnight, quenched withwater (10.0 mL). The mixture was extracted with dichloromethane (3×30.0mL). The combined organic layers was dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo. The residue wassubjected to column chromatography (2% methanol in ethyl acetate/hexane)to give7′-fluoro-1′-[(1-isopropylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(85 mg, 69%) as a white solid, which was treated with 2.0 M HCl indiethyl ether to give the title compound: mp 157-160° C.; ¹H NMR (300MHz, CD₃OD) δ 7.22-7.05 (m, 2H), 7.05-6.98 (m, 1H), 6.52 (s, 1H), 6.21(s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.68 (d, 1H), 3.95-3.77 (m, 2H),3.55-3.42 (m, 3H), 3.12-2.96 (m, 2H), 2.30-2.10 (m, 1H), 2.10-1.97 (m,2H), 1.76-1.52 (m, 2H), 1.34 (d, 6H); ¹³C NMR (75 MHz, CD₃OD) δ 179.7,157.6, 150.6, 150.4, 147.1, 143.9, 136.6, 125.8, 121.2, 120.3, 118.0,103.9, 103.0, 94.3, 81.8, 60.1, 59.7, 47.6, 35.33, 35.30, 28.6, 28.5,16.98, 16.96; MS (ES+) m/z 439.27 (M+1).

Example 10.21 Synthesis of5,5-dimethyl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a solution of5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.09 g, 0.29 mmol) in 2-butanone (10.0 mL) was added2-bromomethyl-5-(trifloromethyl)furan (0.08 g, 0.35 mmol) followed bycesium carbonate (0.19 g, 0.58 mmol) at 0° C. The mixture was stirred atambient temperature overnight. The reaction mixture was filtered and thefiltrate was concentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/5) to give the title compound(0.06 g, 45%): mp 155-160° C.; ¹H NMR (300 MHz, CDCl₃,) δ 7.29 (t, 1H),7.19 (d, 1H), 7.07 (t, 1H), 6.97 (d, 1H), 6.73 (t, 1H), 6.42-6.37 (m,2H), 6.30 (s, 1H), 5.08 (d, 1H), 4.94-4.84 (m, 2H), 4.65 (d, 1H), 4.18(s, 2H), 1.19 (s, 3H), 1.14 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5,161.2, 161.0, 152.0, 141.4, 132.5, 130.1, 128.8, 124.2, 123.8, 120.1,116.4, 112.6, 109.3, 108.7, 93.4, 85.5, 80.6, 57.7, 41.4, 36.9, 27.6,27.5; MS (ES+) m/z 456.5 (M+1).

Example 10.22 Synthesis of5,5-dimethyl-1′-(pyridin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

To a solution of5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.08 g, 0.26 mmol) in DMF (10 mL) was added sodium hydride (0.03 g,0.78 mmol) slowly at 0° C. After 30 min, 3-(bromomethyl)-pyridinehydrobromide (0.10 g, 0.39 mmol) was added. The mixture was stirred atambient temperature overnight, quenched with saturated ammonium chloride(10.0 mL). The mixture was extracted with ethyl acetate (3×20.0 mL). Thecombined organic layers was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo. The residue wassubjected to column chromatography (ethyl acetate/hexane, 2/1) to give5,5-dimethyl-1′-(pyridin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneas a white solid (0.05 g, 48%), which was treated with 2.0 M HCl indiethyl ether to give the title compound: mp 124-126° C.; ¹H NMR (300MHz, CD₃OD) δ 8.96 (br, 1H), 8.82 (br, 1H), 8.62 (d, 1H), 7.3 (t, 1H),7.32 (td, 1H), 7.23-7.17 (m, 1H), 7.16-7.08 (m, 2H), 6.42 (s, 1H), 6.32(s, 1H), 5.35-5.14 (m, 2H), 4.93-4.84 (m, 1H), 4.74 (d, 1H), 4.18 (s,2H), 1.18 (s, 3H), 1.14 (s, 3H); ¹³C NMR (75 MHz, CD₃OD) δ 178.9, 161.6,161.1, 145.4, 141.3, 141.1, 132.5, 130.1, 128.8, 124.0, 123.9, 120.1,116.2, 108.8, 92.6, 85.1, 80.2, 57.8, 41.0, 40.5, 26.5, 26.4; MS (ES+)m/z 399.5 (M+1).

Example 10.23 Synthesis of5,5-dimethyl-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.22, and makingnon-critical variations using 2-(bromomethyl)-pyridine hydrobromide toreplace 3-(bromomethyl)-pyridine hydrobromide, the title compound wasobtained (45%): mp 145-147° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.86 (dd, 1H),8.56 (td, 1H), 8.05-7.97 (m, 2H), 7.37 (td, 1H), 7.31-7.25 (m, 1H),7.24-7.16 (m, 1H), 7.11 (d, 1H), 6.55 (s, 1H), 6.37 (s, 1H), 5.52 (d,1H), 5.38 (d, 1H), 4.97 (d, 1H), 4.79 (d, 1H), 4.23 (s, 2H), 1.24 (s,3H), 1.20 (s, 3H); ¹³C NMR (75 MHz, CD₃OD) δ 177.4, 160.0, 159.6, 150.3,144.7, 141.0, 139.7, 131.0, 128.6, 127.2, 124.3, 123.7, 122.6, 122.4,118.5, 114.8, 107.2, 91.0, 83.6, 78.7, 56.3, 40.1, 39.4, 24.9, 24.8; MS(ES+) m/z 399.5 (M+1).

Example 10.24 Synthesis of1′-[(6-methylpyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.21, and makingnon-critical variations using (6-methylpyridin-3-yl)methyl4-methylbenzenesulfonate to replace2-bromomethyl-5-(trifloromethyl)furan, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-[(6-methylpyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (56%), which was treated with 2.0 M HCl in diethyl ether togive the title compound: ¹H NMR (300 MHz, CD₃OD) δ 8.77 (s, 1H), 8.46(dd, 1H), 7.91 (d, 1H), 7.33 (t, 1H), 7.24-7.09 (m, 3H), 6.52 (s, 1H),6.14 (s, 1H), 5.86 (s, 2H), 5.18 (s, 2H), 4.93-4.85 (m, 1H), 4.71 (d,1H), 2.77 (s, 3H); ¹³C NMR (75 MHz, CD₃OD) δ 180.0, 157.6, 155.1, 150.6,146.6, 143.8, 142.7, 141.2, 135.7, 133.5, 130.3, 129.5, 125.3, 125.2,120.5, 110.3, 103.8, 103.0, 94.3, 81.5, 59.7, 41.5, 19.5; MS (ES+) m/z387.4 (M+1).

Example 10.25 Synthesis of1′-[(6-methoxypyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 10.21, and makingnon-critical variations using (6-methoxypyridin-3-yl)methyl4-methylbenzenesulfonate to replace2-bromomethyl-5-(trifloromethyl)furan, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (45%): ¹H NMR (300 MHz, CDCl₃) δ 8.19(d, 1H), 7.59 (dd, 1H), 7.26-7.12 (m, 2H), 7.02 (t, 1H), 6.83 (d, 1H),6.74 (d, 1H), 6.50 (s, 1H), 6.07 (s, 1H), 5.89-5.82 (m, 2H), 5.00-4.90(m, 2H), 4.76 (d, 1H), 4.65 (d, 1H), 3.93 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 177.6, 163.7, 155.9, 149.0, 145.3, 142.4, 141.6, 138.9, 132.2,129.0, 124.4, 124.1, 123.7, 119.2, 111.7, 109.0, 102.9, 101.5, 93.7,80.4, 58.2, 53.9, 41.1; MS (ES+) m/z 403.2 (M+1).

Example 10.26 Synthesis of1′-[(6-chloropyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations using 2-chloro-5-(chloromethyl)pyridine toreplace 2-bromomethyl-5-(trifloromethyl)furan, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (69%): ¹H NMR (300 MHz, CDCl₃) δ 8.42(d, 1H), 7.63 (dd, 1H), 7.34-7.14 (m, 3H), 7.05 (t, 1H), 6.77 (d, 1H),6.51 (s, 1H), 6.06 (s, 1H), 5.89-5.84 (m, 2H), 5.07-4.78 (m, 3H), 4.66(d, 1H); MS (ES+) m/z 407.3 (M+1).

Example 10.27 Synthesis of1′-{[6-(dimethylamino)pyridin-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

To a seal tube was added1′-((6-chloropyridin-3-yl)methyl)-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one(0.10 g, 0.25 mmol) and dimethylamine (2.00 mL of 2 M THF solution, 4.00mmol). The mixture was stirred at 130° C. overnight. After cooling downto ambient temperature, the mixture was concentrated in vacuo. Theresidue was subjected to column chromatography (ethyl acetate/hexane,1/2) to give1-{[6-(dimethylamino)pyridin-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneas a white solid (50 mg, 48%), which was treated with 2.0 M HCl indiethyl ether to give the title compound: mp 146-150° C.; ¹H NMR (300MHz, CD₃OD) δ 8.03 (d, 1H), 7.95 (dd, 1H), 7.36 (td, 1H), 7.25-7.12 (m,4H), 6.57 (s, 1H), 6.09 (s, 1H), 5.90 (s, 2H), 5.07-4.87 (m, 3H), 4.72(d, 1H), 3.27 (s, 6H); ¹³C NMR (75 MHz, CD₃OD) δ 179.9, 157.6, 154.6,150.5, 143.8, 143.4, 142.9, 137.7, 133.5, 130.2, 125.1, 121.8, 120.6,113.2, 110.4, 103.7, 103.0, 94.3, 81.4, 59.7, 41.1, 39.5; MS (ES+) m/z416.5 (M+1).

Example 10.28 Synthesis of1′-[(6-morpholin-4-ylpyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.27, and makingnon-critical variations using morpholine to replace dimethylaminesolution, the title compound was obtained (52%): mp 185-200° C.; ¹H NMR(300 MHz, CD₃OD) δ 8.13-8.04 (m, 2H), 7.45 (d, 1H), 7.37 (t, 1H),7.26-7.14 (m, 3H), 6.56 (s, 1H), 6.10 (s, 1H), 5.89 (s, 2H), 5.10-4.87(m, 3H), 4.72 (d, 1H), 3.91-3.84 (m, 4H), 3.73-3.67 (m, 4H); ¹³C NMR (75MHz, CD₃OD) δ 180.0, 157.6, 153.7, 150.5, 145.1, 143.8, 142.8, 136.3,133.5, 130.3, 125.2, 125.1, 123.6, 120.6, 114.6, 110.4, 103.7, 103.0,94.3, 81.5, 66.7, 59.7, 47.2, 40.9; MS (ES+) m/z 458.5 (M+1).

Example 10.29 Synthesis of1′-[(6-pyrrolidin-1-ylpyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.27, and makingnon-critical variations using pyrrolidine to replace dimethylaminesolution, the title compound was obtained (45%): mp 160-165° C.; ¹H NMR(300 MHz, CD₃OD) δ 7.99-7.91 (m, 2H), 7.33 (td, 1H), 7.22-7.06 (m, 4H),6.53 (s, 1H), 6.05 (s, 1H), 5.86 (s, 2H), 5.04-4.82 (m, 3H), 4.68 (d,1H), 3.57 (t, 4H), 2.13 (t, 4H); ¹³C NMR (75 MHz, CD₃OD) δ 177.0, 154.6,148.0, 147.6, 141.1, 140.8, 139.9, 132.5, 130.5, 127.3, 122.2, 118.8,117.6, 112.0, 107.4, 100.7, 100.0, 91.3, 78.5, 56.7, 38.0, 23.2; MS(ES+) m/z 442.2 (M+1).

Example 10.30 Synthesis of1′-(2-chloro-4-fluorobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-2-chloro-4-fluorobenzene to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (54%) as a white solid: mp 174-175° C.; MS (ES+) m/z 424.2(M+1).

Example 10.31 Synthesis of1′-[(2-methylcyclopropyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-2-methylcyclopropane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (37%) as a white solid: MS (ES+) m/z 350.3 (M+1).

Example 10.32 Synthesis of1′-(3-cyclopropylpropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and (3-bromopropyl)cyclopropane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (51%) as a white solid: mp 111-113° C.; MS (ES+) m/z 364.3(M+1).

Example 10.33 Synthesis of1′-butylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-bromobutane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan,the title compound was obtained (62%) as a white solid: mp 119-120° C.;MS (ES+) m/z 338.3 (M+1).

Example 10.34 Synthesis of1′-[(5-methylisoxazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 4-(bromomethyl)-5-methylisoxazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (25%) as a white solid: mp 159-161° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.39-6.91 (m, 4H), 6.50 (s, 1H), 6.11 (s, 1H), 5.94 (d, 1H),5.85 (ABq, 2H), 4.95 (ABq, 2H), 4.78 (ABq, 2H), 2.37 (s, 3H); MS (ES+)m/z 377.3 (M+1).

Example 10.35 Synthesis of1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 4-(bromomethyl)tetrahydro-2H-pyran to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (25%) as a white solid: mp 142-144° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.34-6.85 (m, 4H), 6.50 (s, 1H), 6.08 (s, 1H), 5.85 (ABq,2H), 4.76 (ABq, 2H), 4.18-3.86 (m, 2H), 3.63 (ddd, 2H), 3.34 (t, 2H),2.38-1.92 (m, 1H), 1.70-1.36 (m, 4H); MS (ES+) m/z 380.3 (M+1).

Example 10.36 Synthesis of1′-[2-(trifluoromethoxy)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-2-(trifluoromethoxy)benzene to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (77%) as a white solid: mp 130-135° C.; MS (ES+) m/z 456.3(M+1).

Example 10.37 Synthesis of1′[3-(trifluoromethoxy)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-3-(trifluoromethoxy)benzene to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (65%) as a white solid: mp 88-91° C.; MS (ES+) m/z 456.3 (M+1).

Example 10.38 Synthesis of1′4-(trifluoromethoxy)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-4-(trifluoromethoxy)benzene to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (50%) as a white solid: mp 99-101° C.; MS (ES+) m/z 456.3(M+1).

Example 10.39 Synthesis of1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and iodomethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, thetitle compound was obtained (72%) as a white solid: mp 142-144° C.; MS(ES+) m/z 296.2 (M+1).

Example 10.40 Synthesis of1′-Propylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-bromopropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan,the title compound was obtained (64%) as a white solid: mp 158-160° C.;MS (ES+) m/z 324.4 (M+1).

Example 10.41 Synthesis of1′-(2,1,3-benzoxadiazol-5-ylmethyl)spiro[furo2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 5-(bromomethyl)benzo[c][1,2,5]oxadiazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (17%) as a white solid: mp 163-165° C.; MS (ES+) m/z 414.4(M+1).

Example 10.42 Synthesis of1′[(1-methyl-1H-benzotriazol-6-yl)methyl]spiro[furo2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 6-(bromomethyl)-1-methyl-1H-benzotriazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (17%) as a white solid: mp 230-235° C.; MS (ES+) m/z 427.3(M+1).

Example 10.43 Synthesis of tert-butyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine1-carboxylate

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and tert-butyl 4-(bromomethyl)peridine-1-carboxylate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (58%) as a white solid: mp 96-98° C.; ¹H NMR (300 MHz, DMSO-d₆)δ 7.84-6.85 (m, 4H), 6.40 (s, 1H), 6.37 (s, 1H), 4.68 (ABq, 2H), 4.46(t, 2H), 4.06-3.73 (m, 2H), 3.68-3.45 (m, 2H), 2.92 (t, 2H), 2.63 (s,2H), 2.04-1.82 (m, 1H), 1.76-0.66 (m, 13H); MS (ES+) m/z 477.4 (M+1).

Example 10.44 Synthesis of1′-(2,3-difluorobenzyl)-5,6-dihydrospyro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-2,3-difluorobenzene to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (67%) as a white solid: mp 156-158° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.50-6.85 (m, 7H), 6.43 (s, 1H), 6.39 (s, 1H), 5.01 (q, 2H),4.75 (dd, 2H), 4.46 (t, 2H), 2.92 (t, 2H); MS (ES+) m/z 406.2 (M+1).

Example 10.45 Synthesis of1-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-(pyridin-2-ylmethyl)-5,6-dihydrospyro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]2′(1′H)-onewas obtained (27%) as a white solid, which was treated in CH₂Cl₂ withexcess of HCl in ether to give the tilte compound: mp 208-210° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 8.78-8.53 (m, 1H), 8.05 (t, 1H), 7.64-7.47 (m,2H), 7.30-6.92 (m, 4H), 6.59 (s, 1H), 6.38 (s, 1H), 5.24-5.06 (m, 2H),4.78 (ABq, 2H), 4.46 (t, 2H), 2.94 (t, 2H); MS (ES+) m/z 371.4 (M+1).

Example 10.46 Synthesis of1′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 1-(chloromethyl)-4-methoxybenzene to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (56%) as a white solid: mp 120-121° C.; MS (ES+) m/z 400.2(M+1).

Example 10.47 Synthesis of4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.48g, 1.33 mmol) in N,N-dimethylformamide (5.00 mL) was added sodiumhydride (0.08 g, 1.98 mmol, 60% dispersion in mineral oil) in oneportion at 0° C. The reaction mixture was stirred for 0.5 h followed bythe addition of a solution of 2-(bromomethyl)-5-trifluoromethyl)furan inN,N-dimethylformamide (1.00 mL). The reaction mixture was stirred atambient temperature for 16 h and quenched by slow addition of water(5.00 mL). The reaction mixture was extracted with ethyl acetate (3×20.0mL), washed with brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas subjected to column chromatography eluting with ethyl acetate:hexane(35%) to afford the title compound (0.46 g, 69%) as a colorless solid:¹H NMR (300 MHz, CDCl₃) δ 7.22-7.14 (m, 2H), 6.94 (dd, 1H), 6.73 (d,1H), 6.46 (s, 1H), 6.39 (d, 1H), 6.04 (s, 1H) 5.86 (dd, 2H), 4.94 (ABq,2H), 4.92 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.0, 157.2, 151.6,151.5, 149.3, 143.4, 142.2, 130.5, 127.8, 129.6, 120.1, 116.0, 112.7,109.5, 107.9, 102.5, 101.6, 93.3, 77.1, 59.6, 37.1; MS (ES+) m/z 508.2(M+2).

Example 10.48 Synthesis of4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using4′-bromo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, thetitle compound was obtained (76%) as a colorless solid: mp 182-184° C.;¹H NMR (300 MHz, CDCl₃) δ 7.21-7.11 (m, 2H), 6.92 (dd, 1H), 6.74 (d1H),6.41 (d, 1H), 6.38 (s, 1H), 6.37 (s, 1H), 5.10 (d, 1H), 5.02 (d, 1H),4.87 (d, 1H), 4.81 (d, 1H), 4.53 (t, 2H), 2.98 (t, 2H); ¹³C NMR (75 MHz,CDCl₃) δ 177.3, 162.4, 162.2, 151.5, 143.4, 130.2, 127.7, 120.5, 120.0,119.7, 118.4, 117.0, 112.7, 112.6, 109.5, 107.8, 92.9, 77.1, 72.4, 59.1,37.0, 28.9; MS (ES+) m/z 506.3 (M+1).

Example 10.49 Synthesis of4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using iodomethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (79%) as a colorless solid: mp 155-157° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.19 (d, 1H), 7.17 (s, 1H), 6.84 (dd, 1H), 6.46 (s, 1H), 6.08(s, 1H), 5.86 (dd, 2H), 4.90 (ABq, 2H), 3.25 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 177.3, 157.2, 149.2, 145.1, 142.0, 130.4, 129.9, 127.3, 119.9,116.3, 107.3, 102.7, 101.5, 93.3, 77.3, 59.7, 26.9; MS (ES+) m/z 376.4(M+2).

Example 10.50 Synthesis of tert-butyl4-[(4′-bromo-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using tert-butyl4-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (43%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.17 (d,2H), 6.83 (t, 1H), 6.46 (s, 1H), 6.04 (s, 1H), 5.87 (d, 2H), 4.89 (ABq,2H), 4.11 (d, 2H), 3.73-3.42 (m, 3H), 2.66 (t, 2H), 2.03-1.90 (m, 1H),1.43 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 157.3, 154.7, 149.2,144.8, 142.1, 130.3, 129.8, 127.3, 120.2, 116.3, 107.6, 102.4, 101.6,93.4, 79.6, 77.2, 59.6, 46.1, 43.4, 34.9, 28.4; MS (ES+) m/z 581.4(M+23), 579.4 (M+23), 503.3 (M−57), 501.3 (M−57).

Example 10.51 Synthesis of1′-[(3,5-dimethylisoxazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and4-(chloromethyl)-3,5-dimethylisoxazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (35%) as a colorless solid: mp 165-167° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.24 (t, 1H), 7.16 (d, 1H), 7.05 (t, 1H), 6.72 (d, 1H), 6.50(s, 1H), 6.05 (s, 1H), 5.85 (d, 2H), 4.75 (ABq, 2H), 4.67 (ABq, 2H),2.46 (s, 3H), 2.22 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 167.1,159.1, 156.1, 149.1, 142.4, 141.7, 131.8, 129.0, 124.3, 123.8, 118.9,108.8, 108.6, 102.9, 101.6, 93.8, 80.6, 58.2, 33.3, 11.5, 10.7; MS (ES+)m/z 391.3 (M+1).

Example 10.52 Synthesis of1′-(2-furylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and2-chloromethylfuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan,the title compound (40%) as a colorless solid: mp 110-112° C.; ¹H NMR(300 MHz, CDCl₃) δ 7.35-7.33 (m, 1H), 7.29-7.23 (m, 1H), 7.15 (d, 1H),7.06-7.00 (m, 2H), 6.50 (s, 1H), 6.34-6.31 (m, 2H), 6.10 (s, 1H), 5.85(dd, 2H), 4.92 (ABq, 2H), 4.79 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.1, 155.9, 149.0, 148.9, 142.6, 142.3, 141.8, 132.2, 128.9, 123.8,123.5, 119.5, 110.6, 109.3, 108.7, 103.1, 101.5, 93.6, 80.4, 58.2, 37.1;MS (ES+) m/z 362.5 (M+1).

Example 10.53 Synthesis of ethyl5-(2′-oxospiro[furo[2,3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)pentanoate

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, andethyl 5-bromovalerate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (62%) as a gummy material: ¹H NMR (300 MHz, CDCl₃) δ 7.28 (t,1H), 7.14 (d, 1H), 7.03 (t, 1H), 6.88 (d, 1H), 6.48 (s, 1H), 6.13 (s,1H), 5.84 (d, 2H), 4.76 (ABq, 2H), 4.07 (q, 2H), 3.87-3.65 (m, 2H), 2.35(t, 2H), 1.80-1.64 (m, 4H), 1.20 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.4, 173.1, 155.9, 148.8, 142.3, 142.2, 132.5, 128.9, 124.04, 123.3,119.5, 108.6, 103.0, 101.5, 93.6, 80.5, 60.4, 58.2, 39.9, 33.7, 26.8,22.2, 14.2; MS (ES+) m/z 432.09 (M+23).

Example 10.54 Synthesis of ethyl4-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)butanoate

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, andethyl 4-bromobutyrate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (80%) as a gummy material: ¹H NMR (300 MHz, CDCl₃) δ 7.29 (t,1H), 7.14 (d, 1H), 7.04 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 6.18 (s,1H), 5.84 (d, 2H), 4.76 (ABq, 2H), 4.11 (q, 2H), 3.88-3.71 (m, 2H), 2.40(t, 2H), 2.03 (t, 2H), 1.21(t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4,172.8, 156.0, 148.9, 142.4, 142.2, 132.4, 129.0, 124.0, 123.3, 119.4,108.7, 103.0, 101.5, 93.6, 80.5, 60.7, 58.2, 39.6, 31.2, 22.6, 14.3; MS(ES+) m/z 418.08 (M+23), 396.1 (M+1).

Example 10.55 Synthesis of1′-(1,2,4-oxadiazol-3-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and3-(chloromethyl)-1,2,4-oxadiazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (36%)) as a colorless solid: mp 160-162° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.39 (dt, 1H), 7.20-7.13 (m, 3H), 7.05 (d, 1H), 6.50 (s, 1H),6.12 (s, 1H), 5.86 (dd, 2H), 4.78 (ABq, 2H), 4.68 (s, 2H); ¹³C NMR (75MHz, CDCl₃) δ 176.7, 156.0, 149.3, 142.5, 139.6, 131.6, 129.4, 124.8,124.5, 118.4, 113.6, 108.7, 103.0, 101.7, 93.7, 80.3, 58.2, 29.7, 28.0;MS (ES+) m/z 365.2 (M+1).

Example 10.56 Synthesis of1′-{[5-(3-chlorophenyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and2-(chloromethyl)-5-[3-chlorophenyl]furan to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (22%) as a colorless solid: mp 205-207° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.55 (t, 1H), 7.46 (dt, 1H), 7.28 (d, 2H), 7.21-7.14 (m, 2H),7.09-7.04 (m, 2H), 6.59 (d, 1H), 6.50 (s, 1H), 6.40 (d, 1H), 6.10 (s,1H), 5.84 (dd, 2H), 4.98 (ABq, 2H), 4.80 (ABq, 2H); ¹³C NMR (75 MHz,CDCl₃) δ 177.2, 155.9, 152.5, 149.2, 148.9, 142.4, 141.7, 134.8, 132.1,132.0, 130.1, 128.9, 127.5, 124.0, 123.7, 123.6, 121.7, 119.4, 110.8,109.2, 106.9, 103.0, 101.5, 93.6, 80.4, 58.2, 37.3; MS (ES+) m/z 472.2(M+1).

Example 10.57 Synthesis of1′-(3-chloropropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and1-bromo-3-chloropropane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (22%) as a colorless solid: mp 144-146° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.31 (dt, 1H), 7.14-7.12 (m, 2H), 7.01(t, 1H), 6.65 (s, 1H),6.23 (s, 1H), 5.89 (s, 2H), 4.68 (ABq, 2H), 3.85-3.79 (m, 2H), 3.67 (t,2H), 2.06 (t, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.2, 155.8, 148.7,142.9, 142.2, 132.4, 129.3, 124.1, 123.3, 120.3, 109.3, 103.6, 101.7,80.3, 57.8, 43.4, 30.6; MS(ES+) m/z 358.2 (M+1).

Example 10.58 Synthesis of1′-[(2-isopropyl-1,3-oxazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and4-chloromethyl-2-isopropyloxazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (22%) as a colorless solid: mp 118-120° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.97 (s, 1H), 7.24 (t, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 6.98(t, 1H), 6.65 (s, 1H), 6.26 (s, 1H), 5.88 (d, 2H), 4.85 (d, 1H), 4.77(d, 1H), 4.71-4.66 (m, 2H), 3.04-2.95 (m, 1H), 1.18 (dd, 6H); ¹³C NMR(75 MHz, DMSO-d₆) δ 176.9, 169.1, 155.6, 148.7, 142.4, 142.2, 136.8,135.2, 132.4, 129.2, 123.9, 123.4, 120.5, 109.9, 103.6, 101.9, 93.7,79.9, 57.9, 36.2, 28.1, 20.7, 20.6; MS (ES+) m/z 405.2 (M+1).

Example 10.59 Synthesis of1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-1-methyl-1H-benzimidozole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (22%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.71 (d, 1H), 7.65 (d, 1H), 7.54 (t, 1H), 7.39 (t, 1H), 7.30-7.24 (m,1H), 7.16 (d, 1H), 7.05 (d, 2H), 6.63 (s, 1H), 6.49 (s, 1H), 6.44 (d,1H), 6.11 (s, 1H), 5.83 (d, 2H), 4.99 (ABq, 2H), 4.80 (ABq, 2H); ¹³C NMR(75 MHz, CDCl₃) δ 177.2, 155.9, 150.6, 149.6, 148.9, 142.3, 141.7,132.1, 131.8, 129.8, 128.9, 127.9, 126.8, 126.7, 126.6, 123.9, 123.6,119.4, 111.0, 110.9, 110.6, 109.3, 103.1, 101.5, 93.6, 80.4, 58.2, 37.3;MS (ES+) m/z 506.3 (M+1).

Example 10.60 Synthesis of1′-[(2-oxo-1,3-benzothiazol-3(2H)-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3″-indol]-2″(1″H)-one to replace4″-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3″-indol]-2″(1″H)-one, and3-(bromomethyl)-benzo[d]thiazol-2(3H)-one to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (31%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.67(d, 1H), 7.41 (d, 1H), 7.35-7.29 (m, 3H), 7.23-7.14 (m, 2H), 7.05 (t,1H), 6.68 (s, 1H), 5.94-5.85 (m, 5H), 4.69 (td, 1H); ¹³C NMR (75 MHz,DMSO-d₆) δ 178.1, 170.6, 155.9, 148.9, 142.2, 141.0, 136.1, 131.8,129.6, 127.3, 124.5, 124.4, 124.3, 123.7, 121.5, 119.8, 112.1, 110.0,103.4, 101.9, 93.8, 80.3, 58.3, 47.9; MS (ES+) m/z 467.2 (M+23).

Example 10.61 Synthesis of1′-[(5-chloro-2-thienyl)methyl]-5′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using5′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and5-chloro-2-(chloromethyl)thiophene to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (76%) as a colorless solid: mp 142-144° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.22-7.17 (m, 1H), 7.14-7.13 (m, 1H), 7.12-7.10 (m, 2H), 6.96(d, 1H), 6.68 (s, 1H), 6.13 (s, 1H), 5.91 (d, 2H), 5.02 (ABq, 2H), 4.73(ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.9, 161.0, 157.8, 156.0,149.0, 142.2, 138.3, 138.2 (d, ⁴J_(CF)=7.0 Hz) 133.6 (d, ³J_(CF)=33 Hz),128.3, 127.8, 127.1, 119.5, 115.6 (d, ¹J_(CF)=93 Hz), 112.5 (d,¹J_(CF)=100 Hz), 110.8 (d, ³J_(CF)=32 Hz), 103.2, 102.0, 93.9, 79.8,58.2 (d, ⁴hd CF=7.0 Hz), 39.0; MS (ES+) m/z 430.1 (M+1).

Example 10.62 Synthesis of1′-[(5-chloro-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To an ice-cooled solution of (5-chloro-2-furyl)methanol (2.03 g, 15.3mmol) in anhydrous dichloromethane (50.0 mL) was added triethylamine(4.64 g, 45.9 mmol) followed by thionyl chloride (3.64 g, 30.6 mmol).The reaction mixture was stirred at 0° C. for 30 min and quenched withsaturated ammonium chloride (25.0 mL). After the aqueous layer wasseparated, the organic layer was washed with 10% aqueous HCl (20.0 mL),brine (20 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness to give5-chloro-2-chloromethylfuran as a yellow oil. A solution of this oil inanhydrous N,N-dimethylformamide (3.00 mL) was added directly without anyfurther purification to a mixture ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.84 g, 3.00mmol) and sodium hydroxide (0.48 g, 12.0 mmol) in anhydrousN,N-dimethylformamide (9.00 mL). The reaction mixture was heated at 70°C. for 16 h, cooled to ambient temperature followed by the addition ofsaturated ammonium chloride (5.0). N,N-Dimethylformamide was removedunder high vacuum. The residue was diluted with ethyl acetate (100 mL),washed with 10% aqueous HCl (25.0 mL), brine (25.0 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The brown residue was subjected to columnchromatography eluting with ethyl acetate/hexane (35%) to afford thetitle compound (0.74 g, 62%) as a colorless solid: mp 148-150° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 7.29 (t, 1H), 7.15-7.12 (m, 2H), 7.01 (d, 1H),6.67 (s, 1H), 6.60 (d, 1H), 6.39 (d, 1H), 6.10 (s, 1H), 5.89 (d, 2H),4.89 (ABq, 2H), 4.72 (ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.9 155.8149.7, 148.8, 142.2, 142.1, 134.8, 132.1, 129.3 124.1, 123.7 120.2,112.0, 109.9, 108.2 103.2, 101.9, 93.8, 80.0, 57.9 37.0; MS (ES+) m/z396 (M+1).

Example 10.63 Synthesis of1′-[(4-hydroxy-1,2,2,6,6-pentamethylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using5,5,6,7,7-pentamethyl-1-oxa-6-azaspiro[2.5]octane to replace(5-chloro-2-furyl)methanol, the title compound was obtained (70%) as acolorless solid: mp 210-214° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.29 (d,1H), 7.24 (t, 1H), 7.10 (d, 1H), 7.01 (t, 1H), 6.66 (s, 1H), 6.45 (s,1H), 5.90 (d, 2H), 5.20 (br, 1H), 4.70 (ABq, 2H), 3.57 (q, 2H), 3.30 (s,3H), 2.01-1.83 (m, 4H), 1.45 (s, 6H), 1.34 (s, 6H); ¹³C NMR (75 MHz,DMSO-d₆) δ 178.5, 156.0, 148.7, 144.5, 142.2, 132.3, 128.9, 123.8,123.2, 120.3, 110.9, 104.1, 101.9, 93.7, 80.9, 71.6, 65.3, 57.8, 52.6,30.2, 28.7, 22.1; MS (ES+) m/z 465.4 (M+1).

Example 10.64 Synthesis of1′-{(2-chlorophenyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using [5-(2-chlorophenyl)-2-furyl]methanol toreplace (5-chloro-2-furyl)methanol, the title compound was obtained(48%) as a colorless solid: mp 148-150° C.; ¹H NMR (300 MHz, CDCl₃) δ7.74 (d, 1H), 7.39 (d, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 7.19-7.15 (m,2H), 7.08-7.04 (m, 3H), 6.51 (s, 1H), 6.45 (d, 1H), 6.12 (s, 1H), 6.84(s, 2H), 4.99 (ABq, 2H), 4.78 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 155.9, 150.3, 149.0, 148.6, 142.4, 141.8, 132.1, 130.8, 130.0,128.9, 128.7, 128.2, 127.7, 126.9, 123.9, 123.6, 119.4, 111.8, 110.7,109.2, 103.1, 101.5, 93.6, 80.4, 58.2, 37.3; MS (ES+) m/z 472.2 (M+1).

Example 10.65 Synthesis of1′-[(5-methyl-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using (5-methyl-2-furyl)methanol to replace(5-chloro-2-furyl)methanol, the title compound was obtained (70%) as acolorless solid: mp 117-119° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.26 (t,1H), 7.12 (t, 2H), 6.99 (t, 1H), 6.67 (s, 1H), 6.32 (d, 1H), 6.07 (s,1H), 5.97 (d, 1H), 5.89 (d, 2H), 4.84 (ABq, 2H), 4.72 (ABq, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ 176.8, 155.7, 151.9, 148.8, 147.7, 142.3, 142.2,132.1, 129.2, 124.0, 123.5, 120.4, 110.1, 110.0, 107.0, 103.2, 101.9,93.8, 79.9, 57.9, 37.2, 13.7; MS (ES+) m/z 376 (M+1).

Example 10.66 Synthesis of1′-[(5-bromo-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using (5-bromo-2-furyl)methanol to replace(5-chloro-2-furyl)methanol, the title compound was obtained (76%) ascolorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 7.69 (dt,1H), 7.32-7.26 (m, 2H), 7.04 (d, 1H), 6.99 (d, 1H), 6.71 (d, 1H), 6.02(s, 1H), 4.91 (ABq, 2H), 4.47 (t, 2H), 3.08 (t, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.9, 160.4, 156.3, 153.8, 149.7, 146.1, 137.5, 130.9,130.8, 126.5, 125.8, 123.1, 121.5, 118.8, 116.4, 108.3, 96.7, 76.6,71.9, 45.7, 29.1; MS (ES+) m/z 440.1 (M+1), 442.1 (M+1).

Example 10.67 Synthesis of1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using (5-chloro-2-thienyl)methanol to replace(5-chloro-2-furyl)methanol, the title compound was obtained (77%) as acolorless solid: mp 145-146° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.28 (t,1H), 7.20-7.14 (m, 2H), 7.10 (d, 1H), 7.01 (t, 1H), 6.95 (d, 1H), 6.67(s, 1H), 6.09 (s, 1H), 5.89 (d, 2H), 5.02 (ABq, 2H), 4.71 (ABq, 2H); MS(ES+) m/z 411.9 (M+1).

Example 10.68 Synthesis of1′-{[3-hydroxy-5-(trifluoromethyl)-2-thienyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using2-(hydroxymethyl)-5-(trifluoromethyl)thiophene-3-ol to replace(5-chloro-2-furyl)methanol, the title compound was obtained (48%) as acolorless solid: mp 225-227° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.4 (s,1H), 7.29 (dt, 1H), 7.16-7.10 (m, 3H), 7.01 (dt, 1H), 6.68 (s, 1H), 6.09(s, 1H), 5.89 (d, 2H), 4.94 (ABq, 2H), 4.70 (ABq, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.9, 155.8, 152.3, 148.9, 142.2, 141.9, 132.1, 129.4,125.9, 125.4, 124.5, 124.2, 123.8, 122.6, 120.9, 120.0, 116.5, 109.5,103.3, 101.9, 93.8, 80.2, 57.9, 34.9; MS (ES+) m/z 460.38 (M−1).

Example 10.69 Synthesis of1′-{[5-(2-trifluoromethylphenyl)-2-furyl]methyl}-4H-spiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using{5-[2-(trifluoromethyl)phenyl]-2-furyl}methanol to replace(5-chloro-2-furyl)methanol, the title compound was obtained (28%) as acolorless solid: mp 124-126° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, 1H),7.65 (d, 1H), 7.54 (t, 1H), 7.39 (t, 1H), 7.30-7.24 (m, 1H), 7.16 (d,1H), 7.05 (d, 2H), 6.63 (s, 1H), 6.49 (s, 1H), 6.44 (d, 1H), 6.11 (s,1H), 5.83 (d, 2H), 4.99 (ABq, 2H), 4.80 (ABq, 2H); ¹³C NMR (75 MHz,CDCl₃) δ 177.2, 155.9, 150.6, 149.6, 148.9, 142.3, 141.7, 132.1, 131.8,129.8, 128.9, 127.9, 126.8, 126.7, 126.6, 123.9, 123.6, 119.4, 111.0,110.9, 110.6, 109.3, 103.1, 101.5, 93.6, 80.4, 58.2, 37.3; MS (ES+) m/z506.27 (M+1).

Example 10.70 Synthesis of1′[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of (2-chloro-1,3-thiazol-5-yl)methanol (0.30 g, 2.00 mmol)in anhydrous CH₂Cl₂ (20.0 mL) was added thionyl chloride (0.50 g, 4.20mmol) followed by triethylamine (0.40 g, 4.00 mmol) at 0° C. Afterstirring at 0° C. for one hour and ambient temperature for one hour, thereaction mixture was diluted with CH₂Cl₂ (50.0 mL) and extracted withwater (2×20 mL). The organic phase was dried over Na₂SO₄ and filtered.The filtrate was concentrated in vacuo to dryness. The residue wasdissolved in methyl-ethyl ketone (10.0 mL) followed by the additions ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′)-one (0.36 g, 2.00mmol) and cesium carbonate (1.95 g, 6.00 mmol). The reaction mixture washeated at 70° C. overnight, cooled, filtered and the filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography to yield the title compound (0.032 g, 3.4%) as acolorless solid: mp 195-198° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (s,1H), 7.39-6.93 (m, 5H), 6.66 (s, 1H), 6.15-6.12 (m, 1H), 5.89 (d, 2H),5.10 (s, 2H), 4.70 (dd, 2H); MS (ES+) m/z 413.1 (M+1).

Example 10.71 Synthesis of1-{[5-(trifluoromethyl)-2-furyl]methyl}-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 10.21, and makingnon-critical variations using6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (19%) as a white solid: mp 174-177° C.;¹H NMR (300 MHz, DMSO-d₆) δ 7.33-6.95 (m, 5H), 6.84 (s, 1H), 6.71 (d,1H), 5.88 (s, 1H), 5.03 (ABq, 2H), 4.70 (ABq, 2H), 4.46-4.31 (m, 2H),3.07 (t, 2H); MS (ES+) m/z 428.0 (M+1).

Example 10.72 Synthesis of1′{[5-(trifluoromethyl)-2-furyl]methyl}5,6-dihydrospyro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]2′(1′H)-one

Following the procedure described in EXAMPLE 10.21, and makingnon-critical variations using5,6-dihydrospyro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]2′(1′H)-one toreplace5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (71%) as a white solid: mp 173-176° C.;¹H NMR (300 MHz, DMSO-d₆) δ 7.50-6.90 (m, 5H), 6.73 (d, 1H), 6.38 (s,1H), 6.32 (s, 1H), 5.04 (ABq, 2H), 4.75 (ABq, 2H), 4.55-4.36 (m, 2H),2.88 (t, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.2, 161.7, 161.0, 153.5,142.0, 140.3, 139.7, 139.2, 132.6, 129.1, 124.1, 123.8, 121.2, 121.0,120.3, 119.1, 117.7, 114.6, 114.5, 110.4, 109.6, 93.0, 80.0, 72.5, 57.3,36.8, 28.7; MS (ES+) m/z 428.2 (M+1).

Example 10.73 Synthesis of1′-{[5-(trifluoromethyl)-2-thienyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of1-{[3-hydroxy-5-(trifluoromethyl)-2-thienyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.75 g, 1.62 mmol) in anhydrous dichloromethane (12.0 mL) was addedtriethylamine (0.49 g, 0.70 mL, 4.85 mmol) and trifluoromethanesulfonicanhydride (0.91 g, 0.50 mL, 3.24 mmol) at 0° C. under nitrogen. Thereaction mixture was stirred for 30 min and quenched with saturatedammonium chloride (15.0 mL). After the aqueous layer was separated, theorganic layer was washed with 10% HCl (10.0 mL), brine (10.0 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography to provide brown gummy material as the triflate. Amixture of this triflate (15.3 mmol),tetrakis(triphenylphosphine)palladium(0) (0.19 g, 0.17 mmol),triethylamine (1.66 g, 2.30 mL, 16.5 mmol), and formic acid (0.76 mg,0.60 mL, 16.5 mmol) in anhydrous dioxane (24 mL) was heated at refluxfor 16 h. After the reaction mixture was cooled down to ambienttemperature, the solvent was removed under reduced pressure. The blackresidue was diluted with ethyl acetate (50.0 mL), washed with 10% HCl(20.0 mL), saturated ammonium chloride (20.0 mL), brine (20.0 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was subjected to columnchromatography eluting with ethyl acetate:hexane (35%) to afford thetitle compound (0.65 g, 89%) as a colorless solid: mp 127-130° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 7.58-7.56 (m, 1H), 7.32-7.27 (m, 2H), 7.22 (s,1H), 7.18 (d, 1H), 7.16 (s, 1H), 7.09 (dt, 1H), 6.68 (s, 1H), 6.10 (s,1H), 5.89 (d, 2H), 5.17 (ABq, 2H), 4.72 (ABq, 2H); ¹³C NMR (75 MHz,DMSO-d₆) 5 177.0, 155.9, 148.9, 144.7, 142.2, 141.8, 132.1, 130.6,130.5, 129.3, 128.7, 128.0, 124.3, 123.9, 120.0, 109.8, 103.3, 102.0,93.9, 80.2, 57.8, 38.7; MS (ES+) m/z 446.1 (M+1).

Example 10.74 Synthesis of1′-{[3-methoxy-5-(trifluoromethyl)-2-thienyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of1′-{[3-hydroxy-5-(trifluoromethyl)-2-thienyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.18 g, 0.39 mmol), NaOH (0.08 g, 1.96 mmol) and iodomethane (0.17 g,1.18 mmol) in anhydrous N,N-dimethylformamide (2.00 mL) was stirred atambient temperature for 16 h. The reaction was quenched by addition ofsaturated ammonium chloride (10.0 mL) and extracted with ethyl acetate(3×50.0 mL). The combined organic layers was washed with water (3×20.0mL), brine (20.0 mL), dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated in vacuo to dryness. The colorless solidwas triturated with ether to give the title compound (0.15 g, 81%): mp178-180° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (s, 1H), 7.30 (dt, 1H),7.15 (d, 1H), 7.07-7.02 (m, 2H), 6.68 (s, 1H), 6.08 (s, 1H), 5.89 (d,2H), 4.95 (ABq, 2H), 4.70 (ABq, 2H), 3.90 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.0, 155.8, 154.9, 148.9, 142.2, 141.8, 132.1, 129.4,125.7, 124.3, 123.8, 120.4, 120.3, 120.0, 119.5, 109.4, 103.2, 102.0,93.9, 80.1, 59.9, 57.9, 34.9; MS (ES+) m/z 476.3 (M+1).

Example 10.75 Synthesis of4′-methyl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of4′-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indolin]-2′-one(0.51 g, 1.00 mmol), lithium chloride (0.09 mg, 2.00 mmol), Pd₂(dba)₃(0.09 mg, 10 mole%) was flushed with nitrogen. To the above mixture wasadded anhydrous 1-methyl-2-pyrrolidinone (5.00 mL) and tetramethyltin(0.27 mg, 0.20 mL, 1.50 mmol). The reaction mixture was heated at 60° C.for 16 h and quenched with saturated ammonium chloride (10.0 mL). Thereaction mixture was extracted with ethyl acetate (3×10.0 mL). Thecombined organic layers was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas subjected to column chromatography eluting with ethyl acetate:hexane(20%) to afford the title compound (0.07 g, 16%) as a colorless solid:mp 117-119° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.18 (t, 1H), 6.82 (t, 2H),6.72 (d, 1H), 6.47 (s, 1H), 6.37 (d, 1H), 6.09 (s, 1H), 5.86 (d, 2H),4.95 (ABq, 2H), 4.83 (ABq, 2H), 2.03 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.6, 156.2, 152.0, 149.1, 142.3, 141.3, 135.6, 129.4, 128.9, 126.0,120.6, 117.2, 112.7, 112.6, 109.2, 106.5, 102.9, 101.6, 93.3, 78.4,58.3, 37.0, 17.1; MS (ES+) m/z 444.1 (M+1).

Example 10.76 Synthesis of5′-methyl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, thetitle compound was obtained (77%): mp 96-98° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.09 (d, 1H), 7.00 (s, 1H), 6.87 (d, 1H), 6.74 (d, 1H), 6.52 (s, 1H),6.38 (d, 1H), 6.11 (s, 1H), 5.88 (d, 2H), 4.96 (ABq, 2H), 4.80 (ABq,2H), 2.29 (s, 3H); MS (ES+) m/z 444.2 (M+1).

Example 10.77 Synthesis of1′-({5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and3-chloromethyl-5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (44%): ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, 2H), 7.76 (d, 2H),7.30-7.18 (m, 2H), 7.06 (t, 1H), 6.91 (d, 1H), 6.51 (s, 1H), 6.40 (s,1H), 5.88 (s, 2H), 5.17 (ABq, 2H), 4.86 (ABq, 2H); MS (ES+) m/z 508.1(M+1).

Example 10.78 Synthesis of1′-(2-thienylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.62, and makingnon-critical variations using 2-thiophenemethanol to replace(5-chloro-2-furyl)methanol, the title compound was obtained (37%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.20 (m, 2H), 7.18-7.13(m, 1H), 7.10-6.98 (m, 2H), 6.97-6.90 (m, 2H), 6.50 (s, 1H), 6.12 (s,1H), 5.85 (d, 2H), 5.10 (ABq, 2H), 4.79 (ABq, 2H); MS (ES+) m/z 378.19(M+1).

Example 10.79 Synthesis of5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1(2′H)-yl)methyl]thiophene-2-carbonitrile

A mixture of1′-[(5-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.23 g, 0.49 mmol), zinc cyanide (0.07 g, 0.59 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.10 g, 0.11 mmol),1,1′-bis(diphenylphosphino)ferrocene (0.06 g, 0.11 mmol),N,N-dimethylformamide (6.00 mL) and a catalytic amount of water (2drops) was heated at 120° C. for 24 hours. After cooling down to ambienttemperature, the organic solvent was evaporated in vacuo. The residuewas extracted with ethyl acetate (5×15.0 mL) and the combined organicsolution was passed through a bed of celite. The filtrate wassuccessively washed with saturated aqueous ammonium chloride (25.0 mL),water (2×35.0 mL) and brine (40.0 mL). The organic layer was dried oversodium sulfate and filtered. The filtrate was concentrated in vacuo todryness. The residue was subjected to column chromatography eluted with20-35% ethyl acetate in hexanes to afford solid which was furtherpurified by preparative thin layer chromatography, eluted with 20% ethylacetate in hexanes to afford the title compound (0.09 g, 44%): ¹H NMR(300 MHz, CDCl₃) δ 7.50 (d, 1H), 7.32-7.16 (m, 2H), 7.12-7.04 (m, 2H),6.86 (d, 1H), 6.51 (s, 1H), 6.08 (s, 1H), 5.87 (d, 2H), 5.10 (ABq, 2H),4.78 (ABq, 2H); MS (ES+) m/z 403.0 (M+1).

Example 10.80 Synthesis of5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-furonitrile

Following the procedure described in EXAMPLE 10.79, and makingnon-critical variations using1′-[(5-bromo-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace1-[(5-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,the title compound was obtained (44%) as a colorless solid: mp 167-169°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.27 (m, 1H), 7.21-7.17 (m, 1H),7.12-7.08 (m, 1H), 7.07-7.03 (m, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.44(d, 1H), 6.08 (s, 1H), 5.86 (q, 2H), 4.96 (ABq, 2H), 4.78 (ABq, 2H); MS(ES+) m/z 387.2 (M+1).

Example 10.81 Synthesis of1′-{[5-(methylsulfonyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of1′-[(5-bromo-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.70 g, 1.59 mmol), sodium methanesulfinate (85%, 0.23 g, 1.91 mmol),copper (I) iodide (0.04 g, 0.22 mmol), L-proline (0.04 g, 0.35 mmol) anddimethyl sulfoxide (4.00 mL) was heated at 100° C. After 3 days, thereaction mixture was cooled down to ambient temperature, quenched withwater (50.0 mL) and extracted with ethyl acetate (3×40.0 mL). Thecombined organic layers was washed with brine (2×50.0 mL), dried oversodium sulfate and filtered. The filtrate was concentrated in vacuo todryness. The residue was subjected to column chromatography eluting withethyl acetate:hexane (30-50%) to afford the title compound (0.50 g,71%): mp 177-179° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.29 (t, 1H), 7.19 (d,1H), 7.12-7.04 (m, 2H), 6.94 (d, 1H), 6.50 (s, 1H), 6.42 (d, 1H), 6.11(s, 1H), 5.86 (s, 2H), 5.00 (ABq, 2H), 4.79 (ABq, 2H), 3.11 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 177.3, 155.9, 154.5, 149.1, 149.1, 142.4, 141.1,131.9, 129.1, 124.2, 124.1, 119.0, 118.4, 109.9, 108.7, 102.9, 101.6,93.7, 80.3, 58.2, 43.4, 37.2; MS (ES+) m/z 440.0 (M+1).

Example 10.82 Synthesis of1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a mixture of1′-[(6-methoxypyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.23 g, 0.57 mmol), sodium iodide (0.28 g, 1.87 mmol), water (2 drops)in anhydrous acetonitrile (5.00 mL) was added chlorotrimethylsilane(0.19 g, 1.78 mmol) at 0° C. The reaction mixture was stirred at ambienttemperature for 16 h and quenched with sodium bisulfite (0.20 g). Thereaction mixture was diluted with ethyl acetate (100 mL) and washed withbrine (2×25.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue wastriturated with ether (2×10.0 mL) to give the title compound (0.16 g,72%) as la ight yellow solid: mp 247-250° C.; ¹H NMR (300 MHz,DMSO-d_(6,)) δ 11.50 (br, 1H), 7.50 (bd, 1H), 7.36-7.24 (m, 2H),7.17-7.12 (m, 2H), 7.01 (dt, 1H), 6.67 (s, 1H), 6.28 (d, 1H), 6.09 (s,1H), 5.91-5.88 (m, 2H), 4.78 (d, 1H), 4.67-4.62 (m, 3H); MS (ES+) m/z389.15 (M+1).

Example 10.83 Synthesis of1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in PREPARATION 1A, and makingnon-critical variations using1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace 4-bromoindole, and methyl iodide to replace 1-bromopentane,the title compound was obtained (78%): mp 115-118° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.39-7.23 (m, 3H), 7.18 (d, 1H), 7.06 (t, 1H), 6.87 (d, 1H),6.57-6.48 (m, 2H), 6.02 (s, 1H), 5.87-5.83 (m, 2H), 4.90 (d, 1H),4.75-4.52 (m, 3H), 3.51 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 162.5,155.9, 149.1, 142.4, 141.6, 139.7, 137.6, 132.1, 129.1, 124.4, 123.9,121.3, 119.1, 114.0, 108.6, 102.8, 101.6, 93.7, 80.3, 58.2, 40.8, 38.0;MS (ES+) m/z 403.3 (M+1).

Example 10.84 Synthesis of5-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10, and making non-criticalvariations using 5-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and2-chloro-5-(chloromethyl)thiophene to replace 4-fluorobenzyl bromide,the title compound was obtained (95%) as a white solid: mp 140-142° C.;¹H NMR (300 MHz, CDCl₃) δ 7.33-7.26 (m, 2H), 7.16-7.02 (m, 2H), 6.94 (d,1H), 6.97-6.75 (m, 4H), 5.07-4.91 (m, 3H), 4.68 (d, 1H); MS (ES+) m/z446.7 (M+1), 448.7 (M+1).

Example 10.85 Synthesis of1′-[(5-chloro-1,3,4-thiadiazol-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.56 g, 1.99mmol) and (5-chloro-1,3,4-thiadiazol-2-yl)methanol (0.30 g, 1.99 mmol)in anhydrous tetrahydrofuran (12.0 mL) was added tributylphosphine (0.60g, 2.99 mmol) at 0° C. The reaction mixture was stirred for 15 minfollowed by the addition of N,N,N′,N′-tetramethylazodicarboxamide (0.51g, 2.99 mmol). The reaction mixture was stirred at ambient temperatureovernight, quenched with aqueous ammonium chloride (10.0 mL) and dilutedwith ethyl acetate (350 mL). The organic layer was washed with aqueoussaturated sodium chloride (2×25.0 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to column chromatography (ethylacetate/hexane, ½) to give the title compound (0.20 g, 24%) as ayellowish solid: mp 194-197° C.; ¹H NMR (300 MHz, DMSO-d₆,) δ 7.30 (dt,1H), 7.20-7.12 (m, 2H), 7.05 (dt, 1H), 6.67 (s, 1H), 6.28 (s, 1H), 5.90(s, 2H), 5.43 (d, 1H), 5.34 (d, 1H), 4.78 (d, 1H), 4.67 (d, 1H); ¹³C NMR(75 MHz, DMSO-d₆) δ 177.2, 168.3, 155.8, 155.4, 148.9, 142.2, 141.9,132.2, 129.4, 124.2, 124.0, 120.1, 109.8, 103.7, 101.9, 93.8, 80.1,67.5, 57.9, 25.6; MS (ES+) m/z 414.2 (M+1), 416.2 (M+1).

Example 10.86 Synthesis of1′-[(1-pyridin-2-ylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrobromide(0.20 g, 0.44 mmol), 2-bromopyridine (0.16 mL, 0.65 mmol),tetrabutyl ammonium iodide (0.05 g) and DBU (0.16 mL, 1.09 mmol) in DMF(5.00 mL) was heated at 120° C. for 15 hrs. After cooling down toambient temperature, water (30.0 mL) was added. The above mixture wasextracted twice with ethyl acetate (50.0 mL), the combined organic phasewas dried over Na₂SO₄ and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to flash chromatographyeluting with 30% ethyl acetate in hexane to give a white solid (0.05 g,27%): mp 95-97° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.17 (d, 1H), 7.47 (td,1H), 7.31 (t, 1H), 7.18 (d, 1H), 7.06 (t, 1H), 6.92 (d, 1H), 6.66 (d,1H), 6.59 (dd, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.91-5.84 (m, 2H), 4.91(d, 1H), 4.66 (d, 1H), 4.42-4.27 (m, 2H), 3.82-3.53 (m, 2H), 2.85 (t,2H), 2.22-2.05 (m, 1H), 1.85-1.70 (m, 2H), 1.53-1.35 (m, 2H); ¹³C NMR(75MHz, CDCl₃) δ 177.9, 158.8, 156.1, 149.0, 147.4, 142.8, 142.5, 138.0,132.4, 129.1, 124.2, 123.5, 119.5, 112.9, 108.8, 107.7, 103.1, 101.7,93.8, 80.7, 58.3, 46.0, 45.5, 45.4, 35.2, 29.8, 29.7; MS (ES+) m/z 456(M+1).

Example 10.87 Synthesis of1′-[(1-phenyl-2-ylpiperidin-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrobromide (0.20 g, 0.44 mmol), 2-bromobenzene(0.07 mL, 0.65 mmol),Pd₂(dba)₃ (0.03 g, 0.03 mmol), BINAP (0.06 g, 0.10 mmol) and NaOBu^(t)(0.13 g, 1.30 mmol) in toluene was heated at 100° C. for 15 hrs undernitrogen. After cooling down to ambient temperature, water (30.0 mL) wasadded. The above mixture was extracted twice with ethyl acetate (50.0mL), the combined organic phase was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto flash chromatography eluting 30% ethyl acetate in hexane to give awhite solid (0.10 g, 48%): mp 76-78° C.; ¹H NMR (300 MHz, CDCl₃) δ7.37-7.16 (m, 4H), 7.12-6.80 (m, 5H), 6.53 (s, 1H), 6.14 (s, 1H), 5.87(dd, 2H), 4.92 (d, 1H), 4.66 (d, 1H), 3.87-3.55 (m, 4H), 2.72 (t, 2H),2.12-1.94 (m, 1H), 1.89-1.73 (m, 2H), 1.71-1.45 (m, 2H); ¹³C NMR(75 MHz,CDCl₃) δ 177.9, 156.1, 149.0, 142.9, 142.5, 132.4, 129.2, 129.1, 124.2,123.4, 119.9, 119.5, 116.9, 108.8, 103.1, 101.6, 93.8, 80.8, 60.5, 58.3,49.8, 46.1, 34.8, 30.1, 30.0; MS (ES+) m/z 455 (M+1).

Example 10.88 Synthesis of1′-(pyridin-2-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)-2-(trifluoromethyl)furan,1′-(pyridin-2-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained, which was treated with 4.0 M HCl in dioxane to give thetitle compound (39%): mp 150-152° C.; ¹H NMR (300 MHz, CD₃OD) δ8.89-8.78 (m, 1H), 8.62-8.47 (m, 1H), 8.07-7.00 (m, 2H), 7.42-6.70 (m,7H), 5.52-5.31 (m, 2H), 5.05 (d, 1H), 4.89 (d, 1H); ¹³C NMR(75 MHz,CD₃OD) δ 179.4, 163.5, 153.1, 152.7, 148.2, 143.8, 142.8, 133.1, 130.6,129.3, 127.4, 126.8, 125.7, 125.6, 125.4, 114.9, 110.4, 104.9, 82.0,58.9, 43.0; MS (ES+) m/z 413 (M+1).

Example 10.89 Synthesis of1′-(pyridin-3-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one toreplace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and3-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-(pyridin-3-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained, which was treated with 4.0 M HCl in dioxane to give thetitle compound (70%) as a white solid: mp 151-153° C.; ¹H NMR (300 MHz,CD₃OD) δ 9.07-8.61 (m, 3H), 8.19-8.04 (m, 1H), 7.42-6.71 (m, 7H), 5.28(s, 2H), 5.05 (d, 1H), 4.86 (d, 1H); ¹³C NMR (75 MHz, CD₃OD) δ 179.43,163.5, 151.8, 147.0, 142.9, 142.4, 142.2, 133.0, 130.6, 129.3, 128.9,125.5, 125.4, 125.3, 114.9, 110.5, 104.9, 82.0, 58.9, 42.0; MS (ES+) m/z413 (M+1).

Example 10.90 Synthesis of6-(trifluoromethoxy)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one toreplace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, thetitle compound was obtained (82%) as a white solid: mp 78-80° C.; ¹H NMR(300 MHz, CDCl₃) δ 7.33 (td, 1H), 7.21-6.98 (m, 3H), 6.86-6.73 (m, 2H),6.67 (s, 2H), 6.42 (d, 1H), 5.09 (d, 1H), 5.04 (d, 1H), 4.88 (d, 1H),4.77 (d, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 176.7, 161.7, 151.9, 150.6,141.5, 131.7, 129.5, 127.5, 124.2, 124.2, 124.0, 114.1, 112.8, 112.8,109.6, 109.2, 104.3, 80.7, 57.6, 37.1; MS (ES+) m/z 470 (M+1).

Example 10.91 Synthesis of1′-(4-methoxybenzyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations using6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one toreplace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and4-methoxybenzyl chloride to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (91%) as a white solid: mp 82-84° C.; ¹H NMR (300 MHz, CDCl₃) δ7.32-6.80 (m, 9H), 6.68 (s, 2H), 5.06 (d, 1H), 5.03 (d, 1H), 4.80 (d,1H), 4.77 (d, 1H), 3.80 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 171.1, 161.8,159.4, 150.5, 142.3, 132.0, 129.2, 128.9, 127.7, 124.1, 124.0, 123.7,122.2, 118.8, 114.4, 114.1, 109.7, 104.3, 80.9, 57.6, 55.4, 43.9; MS(ES+) m/z 442 (M+1).

Example 10.92 Synthesis of1′-(cyclohexylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, andbromomethyl cyclohexane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (74%) as a white solid: mp 153-154° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.30 (td, 1H), 7.16 (d, 1H), 7.04 (t, 1H), 6.90 (d, 1H), 6.51 (s, 1H),6.14 (s, 1H), 5.90-5.84 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.72-3.44(m, 2H), 1.94-1.60 (m, 6H), 1.32-0.99 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 156.1, 148.9, 143.0, 142.4, 132.5, 128.9, 124.0, 123.2, 119.7,109.0, 103.2, 101.6, 93.7, 80.8, 58.3, 46.8, 36.3, 31.1, 31.0, 26.4,25.9, 25.8; MS (ES+) m/z 378 (M+1), 400 (M+23).

Example 10.93 Synthesis of1′-(methylsulfonyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.47, and makingnon-critical variations usingspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, andmethanesulfonyl chloride to replace2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound wasobtained (51%) as a white solid: mp 215-217° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.83 (d, 1H), 7.42-7.31 (m, 1H), 7.25-7.17 (m, 2H), 6.52 (s, 1H), 6.20(s, 1H), 5.93-5.87 (m, 2H), 4.98 (d, 1H), 4.68 (d, 1H), 3.46 (s, 3H);¹³C NMR (75 MHz, CDCl₃) δ 176.9, 155.8, 149.5, 142.7, 138.1, 130.5,129.7, 125.9, 124.3, 118.5, 113.8, 102.9, 101.8, 93.8, 80.6, 58.8, 41.8;MS (ES+) m/z 360 (M+1), 382 (M+23).

Example 10.94 Synthesis of1′-(2-piperidin-1-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

A mixture of1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.20 g, 0.62 mmol), 1,5-dibromopentane (0.08 mL, 0.62 mmol) andtriethyl amine (0.17 mL, 1.23 mmol) in THF (10.0 mL) was refluxed for 15hrs and concentrated in vacuo to dryness. The residue was subjected toflash chromatography eluting with 10% methanol in ethyl acetate to give1′-(2-piperidin-1-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,which was treated with 4.0 M HCl in dioxane to give the title compound(28%): mp >240° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.40 (t, 1H), 7.27-7.11(m, 3H), 6.51 (s, 1H), 6.17 (s, 1H), 5.86 (s, 2H), 4.91 (d, 1H), 4.71(d, 1H), 4.40-4.13 (m, 2H), 3.95-3.84 (m, 1H), 3.66-3.37 (m, 3H),3.14-2.96 (m, 2H), 2.06-1.45 (m, 6H); ¹³C NMR (75 MHz, CD₃OD) δ 180.4,157.5, 150.5, 143.8, 142.5, 133.9, 130.3, 125.3, 125.1, 120.6, 110.2,103.9, 102.9, 94.2, 81.4, 59.7, 55.4, 54.9, 53.9, 36.4, 24.2, 22.6; MS(ES+) m/z 393 (M+1).

Example 10.95 Synthesis of1′-[2-(pyridin-2-ylamino)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneand1′-[2-(dipyridin-2-ylamino)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 10.87, and makingnon-critical variations using1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and 2-bromopyridine to replace 2-bromobenzene,1′-(2-(pyridin-2-ylamino)ethyl)-spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained as the first fraction from the chromatography as a whitesolid (5%): mp 61-63° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d, 1H),7.50-6.97 (m, 5H), 6.57 (dd, 1H), 6.50 (s, 1H), 6.38 (d, 1H), 6.03 (s,1H), 5.85 (s, 1H), 5.84 (s, 1H), 4.84 (d, 1H), 4.79 (t, 1H), 4.60 (d,1H), 4.15-3.94 (m, 2H), 3.81-3.64 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ178.4, 158.2, 156.0, 149.0, 148.0, 142.4, 142.38, 137.4, 132.3, 129.1,124.0, 123.5, 119.5, 113.3, 109.0, 108.3, 103.2, 101.6, 93.7, 80.5,58.3, 40.1, 39.9; MS (ES+) m/z 402 (M+1).1′-(2-(dipyridin-2-ylamino)ethyl)-spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained as the second fraction from the chromatography (31%): mp165-167° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.31 (dd, 2H), 7.48 (d, 2H), 7.23(t, 1H), 7.09-6.83 (m, 7H), 6.47 (s, 1H), 5.95 (s, 1H), 5.88-5.81(m,2H), 4.73 (d, 1H), 4.67-4.49(m, 2H), 4.46 (d, 1H), 4.20 (t, 2H); ¹³CNMR(75 MHz, CDCl₃) δ 177.6, 157.0, 156.0, 148.8, 148.4, 143.1, 142.3,137.4, 132.3, 128.9, 123.6, 123.1, 119.6, 117.5, 114.5, 109.3, 103.4,101.6, 93.6, 80.7, 58.2, 45.9, 39.5; MS (ES+) m/z 479 (M+1).

Example 10.96 Synthesis of tert-butyl4-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate

Following the procedure as described in EXAMPLE 10, and makingnon-critical variations using tert-butyl4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)piperidine-1-carboxylate toreplace 4-fluorobenzyl bromide, the title compound was obtained in 95%yield: mp 173-175° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.31 (t, 1H), 7.17 (d,1H), 7.06 (t, 1H), 6.88 (d, 1H), 6.51 (s, 1H), 6.10 (s, 1H), 5.90-5.84(m, 2H), 4.90 (d, 1H), 4.65 (d, 1H), 4.0-3.64 (m, 4H), 2.75-2.58 (m,2H), 1.85-1.09 (m, 16H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 156.0, 155.0,149.0, 142.4, 142.2, 132.6, 129.0, 124.2, 123.4, 119.5, 108.6, 103.0,101.6, 93.8, 80.5, 79.5, 58.3, 38.0, 34.0, 33.9, 32.1, 31.9, 28.6; MS(ES+) m/z 515 (M+23), 393 (M−100).

Example 10.97 Synthesis of1′-(2-piperidin-4-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

To a solution of tert-butyl4-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate(0.94 g, 1.91 mmol) in dioxane (5.00 mL) was added 4.0 M HCl in dioxane(2.00 mL, 8.00 mmol). The mixture was stirred at ambient temperature for30 min followed by the addition of anhydrous ether (40.0 mL). Theprecipitated white solid was filtered, washed with ether and dried togive the title compound (0.75 g, 91%): ¹H NMR (300 MHz, CD₃OD) δ 7.37(t, 1H), 7.20-7.07 (m, 3H), 6.52 (s, 1H), 6.10 (s, 1H), 5.86 (s, 2H),4.83 (d, 1H), 4.67 (d, 1H), 3.97-3.75 (m, 2H), 3.45-3.33 (m, 2H),3.01-2.85 (m, 2H), 2.15-2.01 (m, 2H), 1.82-1.37 (m, 5H); ¹³C NMR(75 MHz,CD₃OD) δ 179.8, 157.6, 150.4, 143.7, 143.4, 133.6, 130.3, 124.9, 124.8,120.8, 110.3, 103.7, 102.9, 94.3, 81.4, 59.8, 45.2, 38.5, 34.4, 32.6,29.8, 29.7; MS (ES+) m/z 393 (M+1).

Example 10.98 Synthesis of1′-[2-(1-cyclopentylpiperidin-4-yl)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

To a solution of cyclopentanone (0.04 mL, 0.45 mmol) and triethyl amine(0.12 mL, 0.84 mmol) in dichloroethane (5.00 mL) was added1′-(2-piperidin-4-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride (0.12 g, 0.28 mmol) and sodium triacetoxyborohydride (0.10g, 0.45 mmol). The reaction mixture was stirred for 16 hrs andconcentrated in vacuo to dryness. The residue was subjected to flashchromatography eluting with ethyl acetate/methanol/ammonium hydroxide(15/1/0.1) to give1′-[2-(1-cyclopentylpiperidin-4-yl)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneas a white solid, which was treated with 4.0 M HCl in dioxane to givethe title compound (0.05 g, 32% yield): mp 153-155° C.; ¹H NMR (300 MHz,CD₃OD) δ 7.37 (td, 1H), 7.21-7.08 (m, 3H), 6.53 (s, 1H), 6.11 (s, 1H),5.88 (s, 1H), 5.87 (s, 1H), 4.83 (d, 1H), 4.69 (d, 1H), 3.98-3.75 (m,2H), 3.68-3.38 (m, 3H), 3.01-2.83 (m, 2H), 2.25-2.08 (m, 4H), 1.92-1.37(m, 11H); ¹³C NMR (75 MHz, CD₃OD) δ 179.8, 157.6, 150.4, 143.8, 143.4,133.6, 130.3, 124.9, 124.8, 120.8, 110.3, 103.7, 103.0, 94.3, 81.4,69.1, 59.8, 53.2, 38.6, 34.3, 32.5, 30.6, 30.5, 29.4, 24.7; MS (ES+) m/z461 (M+1).

Example 10.99 Synthesis of1′-[2-(1-isopropylpiperidin-4-yl)ethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.98, and makingnon-critical variations using acetone to replace cyclopentanone, thetitle compound was obtained (42%) as a white solid: mp 155-156° C.; ¹HNMR (300 MHz, CD₃OD) δ 7.37 (t, 1H), 7.21-7.08 (m, 3H), 6.53 (s, 1H),6.11 (s, 1H), 5.87 (s, 2H), 4.84 (d, 1H), 4.69 (d, 1H), 3.98-3.75 (m,2H), 3.58-3.38 (m, 3H), 3.05-2.85 (m, 2H), 2.23-2.09 (m, 2H), 1.82-1.44(m, 5H), 1.35 (d, 6H); ¹³C NMR (75 MHz, CD₃OD) δ 179.8, 157.6, 150.5,143.8, 143.4, 133.6, 130.3, 125.0, 124.8, 120.8, 110.3, 103.7, 103.0,94.3, 81.4, 59.8, 59.6, 38.6, 34.2, 32.7, 30.6, 30.5, 24.2, 16.9. 15.4;MS (ES+) m/z 435 (M+1).

Example 10.100 Synthesis of1′-[2-(1-cyclobutylpiperidin-4-yl)ethyl]spiro[furo[2,3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrochloride

Following the procedure as described in EXAMPLE 10.98, and makingnon-critical variations using cyclobutanone to replace cyclopentanone,the title compound was obtained (81%) as a white solid: mp 158-160° C.;¹H NMR (300 MHz, CD₃OD) δ 7.37 (t, 1H), 7.21-7.05 (m, 3H), 6.52 (s, 1H),6.10 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 (d, 1H), 3.98-3.39 (m,5H), 2.85-2.59 (m, 2H), 2.43-1.42 (m, 13H); ¹³C NMR (75 MHz, CD₃OD) δ179.8, 157.6, 150.4, 143.7, 143.4, 133.6, 130.3, 124.9, 124.8, 120.8,110.4, 103.8, 103.0, 94.2, 81.5, 60.5, 59.8, 50.8, 38.6, 34.4, 32.5,30.1, 26.8, 14.4; MS (ES+) m/z 447 (M+1).

Example 10.101 Synthesis of1′-{2-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 10.98, and makingnon-critical variations using tetrahydro-4H-pyran-4-one to replacecyclopentanone, the title compound was obtained (45%) as a white solid:mp 168-170° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.37 (t, 1H), 7.21-7.06 (m,3H), 6.52 (s, 1H), 6.11 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 (d,1H), 4.12-3.31 (m, 9H), 3.05-2.85 (m, 2H), 2.25-1.45 (m, 11H); ¹³C NMR(75 MHz, CD₃OD) δ 179.8, 157.6, 150.4, 143.7, 143.4, 133.6, 130.3,125.0, 124.8, 120.8, 110.3, 103.8, 102.9, 94.3, 81.4, 67.2, 64.1, 59.8,50.7, 38.6, 34.2, 32,7, 30.6, 30.5, 28.7; MS (ES+) m/z 477 (M+1).

Example 11 Synthesis of4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

Following the procedure described in EXAMPLE 6, and making non-criticalvariations using methyl4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoateto replace methyl2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate,the title compound was obtained (100%): ¹H NMR (300 MHz, CDCl₃) δ 12.96(s, 1H), 7.90 (d, 2H), 7.43 (d, 2H), 7.22 (t, 1H), 7.17 (d, 1H), 7.00(t, 1H), 6.94 (d, 1H), 6.68 (s, 1H), 6.21 (s, 1H), 5.90 (s, 2H), 4.98(s, 2H), 4.76 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 167.5, 156.0,148.9, 142.6, 142.3, 141.8, 132.1, 130.5, 130.3, 129.3, 127.7, 124.2,123.7, 120.1, 109.9, 103.5, 101.9, 93.8, 80.4, 58.0, 43.4.

Example 12 Synthesis ofN-(3-fluorophenyl)-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

A. Preparation of stock solution of4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoylchloride

To a stirred slurry of4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (2.08 g, 5.00 mmol) in dry chloroform (50.0 mL) was added oxalylchloride (0.95 g, 7.50 mmol) at ambient temperature followed by 1 dropof DMF. The mixture was stirred at ambient temperature for 2 h andevaporated to dryness in vacuo. The residue was dissolved in drydichlormethane (60.0 mL) to form an acid chloride stock solution foruse.

B. Synthesis ofN-(3-fluorophenyl)-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

To a solution of 3-fluorophenylamine (0.02 mL, 0.24 mmol) in drydichloromethane (2.00 mL) and triethylamine (0.05 mL, 0.32 mmol) wasadded the acid chloride stock solution (2.0 mL, 0.081 M indichloromethane) obtained above at ambient temperature. The mixture wasstirred for 2 h, washed with 15% HCl solution and water. The organiclayer was separated, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was dissolved in ethylacetate, and the product was precipitated by the addition of hexane. Thewhite solid was filtered and collected to yield the title compound (0.06g) in 70% yield: ¹H NMR (300 MHz, CDCl₃) δ 8.30 (s, 1H), 7.83 (d, 2H),7.58 (ddd, 1H), 7.38 (d, 2H), 7.27-7.23 (m, 2H), 7.21-7.16 (m, 2H), 7.04(dt, 1H), 6.85-6.78 (m, 1H), 6.74 (d, 1H), 6.46 (s, 1H), 6.10 (s, 1H),5.77 (d, 1H), 5.68 (d, 1H), 4.97 (ABq, 2H), 4.76 (ABq, 2H); MS (ES+),m/z 509.1 (M+1).

Example 12.1

The compounds listed in the following table were prepared using thesimilar procedure as described in EXAMPLE 12. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound Number Name MS (m/z, M + 1) 500N-butyl-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 471.27,3′-indol]-1′(2′H)-yl)methyl]benzamide 501N-(3-fluorobenzyl)-4-[(2′-oxospiro[furo[2,3- 523.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5021′-[4-(piperidin-1-ylcarbonyl)benzyl]spiro[furo[2,3- 483.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 503N,N-diisopropyl-4-[(2′-oxospiro[furo[2,3- 499.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 504N-(4-chlorobenzyl)-4-[(2′-oxospiro[furo[2,3- 540.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 505N-(3-chlorophenyl)-4-[(2′-oxospiro[furo[2,3- 526.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 506N-(2-fluorophenyl)-4-[(2′-oxospiro[furo[2,3- 509.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 507N-(2-ethylphenyl)-4-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 508N-(4-ethylphenyl)-4-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 509N-(4-methylphenyl)-4-[(2′-oxospiro[furo[2,3- 505.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 510N-(3,5-dimethylphenyl)-4-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 511N-(2,3-dimethylphenyl)-4-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5124-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 485.11′(2′H)-yl)methyl]-N-pentylbenzamide 5134-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 457.11′(2′H)-yl)methyl]-N-propylbenzamide 514N-isopropyl-4-[(2′-oxospiro[furo[2,3- 457.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 515N-isobutyl-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 471.17,3′-indol]-1′(2′H)-yl)methyl]benzamide 516N-hexyl-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 499.27,3′-indol]-1′(2′H)-yl)methyl]benzamide 517N-cyclohexyl-4-[(2′-oxospiro[furo[2,3- 497.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 518N-cyclopentyl-4-[(2′-oxospiro[furo[2,3- 483.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 519N-heptyl-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 513.27,3′-indol]-1′(2′H)-yl)methyl]benzamide 520N-(2-methoxybenzyl)-4-[(2′-oxospiro[furo[2,3- 535.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 521N-(2,6-dimethylphenyl)-4-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 522N-(2-methoxyphenyl)-4-[(2′-oxospiro[furo[2,3- 521.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 523N-cyclopropyl-4-[(2′-oxospiro[furo[2,3- 455.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 524N-(3-methoxypropyl)-4-[(2′-oxospiro[furo[2,3- 487.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5254-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 491.21′(2′H)-yl)methyl]-N-phenylbenzamide 526N-(2,4-dimethylphenyl)-4-[(2′-oxospiro[furo[2,3- 519.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5274-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 499.21′(2′H)-yl)methyl]-N-(tetrahydrofuran-2- ylmethyl)benzamide 528N,N-dibenzyl-4-[(2′-oxospiro[furo[2,3- 595.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 529N-[2-(diethylamino)ethyl]-4-[(2′-oxospiro[furo[2,3- 514.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 530N-methyl-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 429.27,3′-indol]-1′(2′H)-yl)methyl]benzamide 5314-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 559.11′(2′H)-yl)methyl]-N-[3- (trifluoromethyl)phenyl]benzamide 532N-ethyl-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 443.17,3′-indol]-1′(2′H)-yl)methyl]benzamide 533N-(3-ethoxypropyl)-4-[(2′-oxospiro[furo[2,3- 501.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 534N-(4-methoxybenzyl)-4-[(2′-oxospiro[furo[2,3- 535.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 535N-(3,5-dichlorophenyl)-4-[(2′-oxospiro[furo[2,3- 560.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5364-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 492.21′(2′H)-yl)methyl]-N-pyridin-3-ylbenzamide 537N-(4-cyanophenyl)-4-[(2′-oxospiro[furo[2,3- 516.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 538N-(4-methylpentyl)-4-[(2′-oxospiro[furo[2,3- 499.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5394-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 497.21′(2′H)-yl)methyl]-N-(2,2,2- trifluoroethyl)benzamide 5404-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 506.11′(2′H)-yl)methyl]-N-(pyridin-4- ylmethyl)benzamide 541N-[2-(3-chlorophenyl)ethyl]-4-[(2′-oxospiro[furo[2,3- 554f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 542N-(2-furylmethyl)-4-[(2′-oxospiro[furo[2,3- 495.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 543N-(3-fluoro-2-methylphenyl)-4-[(2′-oxospiro[furo[2,3- 523.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 544N-hexyl-N-methyl-4-[(2′-oxospiro[furo[2,3- 513.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 545N-(3-isopropoxypropyl)-4-[(2′-oxospiro[furo[2,3- 515.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 546N-(2-ethoxyethyl)-4-[(2′-oxospiro[furo[2,3- 487.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 547N-(cyclopropylmethyl)-4-[(2′-oxospiro[furo[2,3- 469.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 548N-(4-methoxyphenyl)-4-[(2′-oxospiro[furo[2,3- 521.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 549N-cyclobutyl-4-[(2′-oxospiro[furo[2,3- 469.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 550N-(2,2-diphenylethyl)-4-[(2′-oxospiro[furo[2,3- 595.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 551N-[2-(4-fluorophenyl)ethyl]-4-[(2′-oxospiro[furo[2,3- 537.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 552N-(cyclohexylmethyl)-4-[(2′-oxospiro[furo[2,3- 511.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 553N-(2-fluoro-4-methylphenyl)-4-[(2′-oxospiro[furo[2,3- 523.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 554N-[2-(4-methylphenyl)ethyl]-4-[(2′-oxospiro[furo[2,3- 533.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 555N-(2-ethylbutyl)-4-[(2′-oxospiro[furo[2,3- 499.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 556N-benzyl-4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 505.17,3′-indol]-1′(2′H)-yl)methyl]benzamide 557N-(2-methoxyethyl)-4-[(2′-oxospiro[furo[2,3- 473.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5581′-[4-(morpholin-4-ylcarbonyl)benzyl]spiro[furo[2,3- 485.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 559N-(1-benzylpiperidin-4-yl)-4-[(2′-oxospiro[furo[2,3- 588.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 560N-[2-(4-methoxyphenyl)ethyl]-4-[(2′-oxospiro[furo[2,3- 549.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5614-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 559.11′(2′H)-yl)methyl]-N-[2- (trifluoromethyl)phenyl]benzamide 562N-[4-chloro-2-(trifluoromethyl)phenyl]-4-[(2′- 594.1oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 563N-[4-fluoro-2-(trifluoromethyl)phenyl]-4-[(2′- 577.1oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 564N-(2-cyanoethyl)-4-[(2′-oxospiro[furo[2,3- 468.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 565N-[(1S)-1-cyclohexylethyl]-4-[(2′-oxospiro[furo[2,3- 525.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 566N-[(1R)-1-cyclohexylethyl]-4-[(2′-oxospiro[furo[2,3- 525.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 567N-(2,4-difluorophenyl)-4-[(2′-oxospiro[furo[2,3- 527.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 568N-(2,3-dihydro-1H-inden-1-yl)-4-[(2′-oxospiro[furo[2,3- 531.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5694-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 511.21′(2′H)-yl)methyl]-N-(2-thienylmethyl)benzamide 570N-[(1-ethylpyrrolidin-2-yl)methyl]-4-[(2′- 526.2oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 5714-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 533.21′(2′H)-yl)methyl]-N-(4-propylphenyl)benzamide 572N-(2,5-difluorobenzyl)-4-[(2′-oxospiro[furo[2,3- 541.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 573N-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxospiro[furo[2,3- 531.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 574N-(2,5-difluorophenyl)-4-[(2′-oxospiro[furo[2,3- 527.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5754-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 573.11′(2′H)-yl)methyl]-N-[4- (trifluoromethyl)benzyl]benzamide 5764-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 525.11′(2′H)-yl)methyl]-N-[2-(2-thienyl)ethyl]benzamide 5774-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 506.21′(2′H)-yl)methyl]-N-(pyridin-3- ylmethyl)benzamide 5784-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 573.11′(2′H)-yl)methyl]-N-[2- (trifluoromethyl)benzyl]benzamide 579N-[2-(4-chlorophenyl)ethyl]-4-[(2′-oxospiro[furo[2,3- 554f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5804-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 512.21′(2′H)-yl)methyl]-N-(2-pyrrolidin-1- ylethyl)benzamide 581N-(3-methylpyridin-2-yl)-4-[(2′-oxospiro[furo[2,3- 506.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 582N-[3-(dimethylamino)propyl]-N-methyl-4-[(2′- 514.2oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide 583N-1,3-benzodioxol-5-yl-4-[(2′-oxospiro[furo[2,3- 535.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 584N-(2-morpholin-4-ylethyl)-4-[(2′-oxospiro[furo[2,3- 528.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5851′-{4-[(4-pyrimidin-2-ylpiperazin-1- 562.2yl)carbonyl]benzyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 5864-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 498.11′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide 587N-(6-methoxypyridin-3-yl)-4-[(2′-oxospiro[furo[2,3- 522.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 588N-(3,5-dichlorobenzyl)-4-[(2′-oxospiro[furo[2,3- 574.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 589N-1-naphthyl-4-[(2′-oxospiro[furo[2,3- 541.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5901′-(4-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1- 618.2yl]carbonyl}benzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 591N-(4,6-dimethylpyridin-2-yl)-4-[(2′-oxospiro[furo[2,3- 520.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5924-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 493.11′(2′H)-yl)methyl]-N-pyrimidin-4-ylbenzamide 593N-(5-methyl-1,3-thiazol-2-yl)-4-[(2′-oxospiro[furo[2,3- 512.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 594N-(2-cyano-6-fluorophenyl)-4-[(2′-oxospiro[furo[2,3- 534.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 595N-(4-methylbenzyl)-4-[(2′-oxospiro[furo[2,3- 519.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 596N-[3-(1H-imidazol-1-yl)propyl]-4-[(2′-oxospiro[furo[2,3- 523.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 597N-(4-morpholin-4-ylphenyl)-4-[(2′-oxospiro[furo[2,3- 576.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)methyl]benzamide 5981′-{4-[(4-methylpiperazin-1- 498.2 yl)carbonyl]benzyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 599N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-[(2′- 539.2oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzamide

Example 13 Synthesis of1′-(3-hydroxypropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A suspension of1′-[3-(benzyloxy)propyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(6.27 g, 14.5 mmol) and 10% Pd/C (0.5 g) in MeOH (150 mL) washydrogenated under the normal pressure of hydrogen overnight andfiltered through a pad of celite. The filtrate was concentrated in vacuoto dryness. The residue was crystallized from ether to yield the titlecompound (4.82 g) as a white solid in 98% yield: ¹H NMR (300 MHz, CDCl₃)δ 7.38-6.93 (m, 4H), 6.49 (s, 1H), 6.10 (s, 1H), 4.87 (m, 1H), 4.63 (m,1H), 4.01-3.81 (m, 2H), 3.62 (t, 2H), 2.89 (br, 1H), 1.99-1.91(m, 2H);¹³C NMR (75 MHz, CDCl₃) δ 178.8, 156.0, 148.9, 142.4, 142.1, 132.3,129.0, 128.9, 124.1, 123.9, 119.0, 108.6, 103.0, 101.5, 93.6, 80.4,58.3, 37.8, 29.8; MS (ES+) m/z 340.2 (M+1).

Example 14 Synthesis of3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanal

To a solution of1′-(3-hydroxypropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(4.82 g, 14.2 mmol) in dichloromethane (150 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (7.00 g, 16.7mmol) at 0° C. The resulting mixture was stirred at 0° C. for 4 h,diluted with ethyl acetate, washed sequentially with 10% Na₂S₂O₃solution, saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas subjected to flash chromatography and the product was recrystallizedfrom ethyl acetate/hexanes to afford the title compound (3.86 g) in 80%yield: ¹H NMR (300 MHz, CDCl₃) δ 9.83 (s, 1H), 7.33-6.92 (m, 4H), 6.48(s, 1H), 6.08 (s, 1H), 4.86 (m, 1H), 4.61(m, 1H), 4.15-3.98 (m, 2H),2.97-2.84 (m, 2H); MS (ES+, m/z) 338.1 (M+1).

Example 15 Synthesis of1′-{3-[(cyclopropylmethyl)amino]propyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanal(0.07 g, 0.20 mmol) in THF (5.00 mL) was added (aminomethyl)cyclopropane(0.30 mmol) and MP-triacetoxyborohydride (0.26 g, 0.60 mmol). Afterovernight shaking, the polymer-bound 4-phenyloxybenzaldehyde (0.25 g,0.18 mmol) was added. After another overnight shaking, the mixture wasdiluted with ether (10.0 mL) and filtered. The filtrate was concentratedin vacuo to dryness. The residue was recrystallized to give the titlecompound (0.05 g) in 62% yield as a white solid: ¹H NMR (300 MHz, CDCl₃)δ 7.32-6.92 (m, 4H), 6.49 (s, 1H), 6.12 (s, 1H), 5.83 (m, 2H), 4.86 (m,1H), 4.64 (m, 1H), 3.97-3.77(m, 2H), 2.87-2.80 (m, 2H), 2.66-2.56 (m,2H), 1.02-0.94 (m, 1H), 0.56-0.47 (m, 2H), 0.25-0.18 (m, 2H); MS (ES+)m/z 393.3 (M+1).

Example 15.1

The compounds listed in the following table were prepared using thesimilar procedure as described in EXAMPLE 15. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound Number Name MS (m/z, M + 1) 6001′-{3-[(4-fluorobenzyl)amino]propyl}spiro[furo[2,3- 447.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6011′-{3-[(4-chlorophenyl)amino]propyl}spiro[furo[2,3- 449.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6021′-[3-(pentylamino)propyl]spiro[furo[2,3- 409.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6031′-{3-[(2-ethoxyethyl)amino]propyl}spiro[furo[2,3- 411.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6041′-{3-[(3-methoxypropyl)amino]propyl}spiro[furo[2,3- 411.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6051′-{3-[(3-methylbutyl)amino]propyl}spiro[furo[2,3- 409.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6061′-{3-[(3-ethoxypropyl)amino]propyl}spiro[furo[2,3- 425.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6071′-{3-[(2,2-dimethylpropyl)amino]propyl}spiro[furo[2,3- 409.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6083-{[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 392.41′(2′H)-yl)propyl]amino}propanenitrile 6091′-{3-[(2,2,2-trifluoroethyl)amino]propyl}spiro[furo[2,3- 421.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6101′-[3-(cyclopropylamino)propyl]spiro[furo[2,3- 379.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6111′-[3-(cyclobutylamino)propyl]spiro[furo[2,3- 393.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6121′-{3-[(2-cyclopropylethyl)amino]propyl}spiro[furo[2,3- 407.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6131′-[3-(isobutylamino)propyl]spiro[furo[2,3- 395.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6141′-[3-(hexylamino)propyl]spiro[furo[2,3-f][1,3]benzodioxole- 423.57,3′-indol]-2′(1′H)-one 615 1′-[3-(heptylamino)propyl]spiro[furo[2,3-437.1 f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6161′-[3-(isopropylamino)propyl]spiro[furo[2,3- 381.7f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6171′-{3-[(tetrahydrofuran-2- 423.1 ylmethyl)amino]propyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6181′-[3-(benzylamino)propyl]spiro[furo[2,3- 429.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6191′-{3-[(2-phenylethyl)amino]propyl}spiro[furo[2,3- 443.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6201′-[3-(dibenzylamino)propyl]spiro[furo[2,3- 519.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6211′-[3-(propylamino)propyl]spiro[furo[2,3- 381.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6221′-(3-{[2-(3-fluorophenyl)ethyl]amino}propyl)spiro[furo[2,3- 461.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6231′-{3-[(3-phenylpropyl)amino]propyl}spiro[furo[2,3- 457.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6241′-{3-[(2,2-diphenylethyl)amino]propyl}spiro[furo[2,3- 519.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6251′-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)spiro[furo[2,3- 457.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6261′-(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)spiro[furo[2,3- 477.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6271′-{3-[(2-pyridin-4-ylethyl)amino]propyl}spiro[furo[2,3- 444.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6281′-{3-[(pyridin-4-ylmethyl)amino]propyl}spiro[furo[2,3- 430.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6291′-(3-{[2-(4-fluorophenyl)ethyl]amino}propyl)spiro[furo[2,3- 461.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6301′-{3-[(pyridin-2-ylmethyl)amino]propyl}spiro[furo[2,3- 430.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6311′-(3-{[(1R)-1-cyclohexylethyl]amino}propyl)spiro[furo[2,3- 449.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6321′-{3-[(2-furylmethyl)amino]propyl}spiro[furo[2,3- 419.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6331′-{3-[(4-chlorobenzyl)amino]propyl}spiro[furo[2,3- 463.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6341′-{3-[(4-methoxybenzyl)amino]propyl}spiro[furo[2,3- 459.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6351′-{3-[(3-isopropoxypropyl)amino]propyl}spiro[furo[2,3- 439.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6361′-(3-{[2-(2-fluorophenyl)ethyl]amino}propyl)spiro[furo[2,3- 461.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6371′-{3-[(3,3-dimethylbutyl)amino]propyl}spiro[furo[2,3- 423.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6381′-{3-[(cyclohexylmethyl)amino]propyl}spiro[furo[2,3- 435.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6391′-(3-{[(1S)-1-cyclohexylethyl]amino}propyl)spiro[furo[2,3- 436.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6401′-{3-[(2-piperidin-1-ylethyl)amino]propyl}spiro[furo[2,3- 449.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6411′-{3-[(2-pyrrolidin-1-ylethyl)amino]propyl}spiro[furo[2,3- 450.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6421′-{3-[(2-morpholin-4-ylethyl)amino]propyl}spiro[furo[2,3- 452.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6431′-[3-(cyclohexylamino)propyl]spiro[furo[2,3- 421.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6441′-[3-(cyclopentylamino)propyl]spiro[furo[2,3- 407.3f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6451′-{3-[(2-chlorobenzyl)amino]propyl}spiro[furo[2,3- 463.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6461′-(3-pyrrolidin-1-ylpropyl)spiro[furo[2,3- 393.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6471′-[3-(dibutylamino)propyl]spiro[furo[2,3- 451.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6481′-(3-piperidin-1-ylpropyl)spiro[furo[2,3- 407.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6491′-[3-(dipropylamino)propyl]spiro[furo[2,3- 423.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6501′-(3-{[2-(dimethylamino)ethyl]amino}propyl)spiro[furo[2,3- 410.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 651 1′-(3-{[2- 452.1(diethylamino)ethyl](methyl)amino}propyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 652 1′-(3-{[2- 466.1(diisopropylamino)ethyl]amino}propyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6531′-[3-(diisopropylamino)propyl]spiro[furo[2,3- 423.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6541′-[3-(methylamino)propyl]spiro[furo[2,3- 353.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6551′-[3-(ethylamino)propyl]spiro[furo[2,3-f][1,3]benzodioxole- 367.07,3′-indol]-2′(1′H)-one 6561′-{3-[bis(2-methoxyethyl)amino]propyl}spiro[furo[2,3- 455.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6571′-{3-[(2-fluorobenzyl)amino]propyl}spiro[furo[2,3- 446.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6581′-{3-[(3,5-difluorobenzyl)amino]propyl}spiro[furo[2,3- 464.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 659 1′-(3-{[3- 424.0(dimethylamino)propyl]amino}propyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6601′-[3-(diethylamino)propyl]spiro[furo[2,3- 394.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6611′-[3-(octylamino)propyl]spiro[furo[2,3-f][1,3]benzodioxole- 451.57,3′-indol]-2′(1′H)-one 6621′-{3-[(1-methylbutyl)amino]propyl}spiro[furo[2,3- 409.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6631′-{3-[butyl(methyl)amino]propyl}spiro[furo[2,3- 409.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6641′-{3-[(2-isopropoxyethyl)amino]propyl}spiro[furo[2,3- 425.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6651′-{3-[(2,4-difluorobenzyl)amino]propyl}spiro[furo[2,3- 464.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6661′-{3-[(2-methylbenzyl)amino]propyl}spiro[furo[2,3- 443.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6671′-{3-[(3-fluorobenzyl)amino]propyl}spiro[furo[2,3- 446.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6681′-{3-[(2,6-difluorobenzyl)amino]propyl}spiro[furo[2,3- 464.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6691′-{3-[(1,2-dimethylpropyl)amino]propyl}spiro[furo[2,3- 409.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6701′-(3-{[2-(1-methylpyrrolidin-2- 450.4yl)ethyl]amino}propyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6711′-{3-[(2-pyridin-3-ylethyl)amino]propyl}spiro[furo[2,3- 444.5f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6721′-{3-[(1-methyl-2-phenylethyl)amino]propyl}spiro[furo[2,3- 457.0f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6731′-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)spiro[furo[2,3- 476.9f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6741′-{3-[(2-cyclohexylethyl)amino]propyl}spiro[furo[2,3- 448.1f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6751′-{3-[(2-pyridin-2-ylethyl)amino]propyl}spiro[furo[2,3- 444.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6761′-{3-[(2-biphenyl-4-ylethyl)amino]propyl}spiro[furo[2,3- 519.6f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6771′-{3-[(3-morpholin-4-ylpropyl)amino]propyl}spiro[furo[2,3- 466.2f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 678 1′-(3-{[(5-methyl-2-433.3 furyl)methyl]amino}propyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6791′-{3-[(3-methylbenzyl)amino]propyl}spiro[furo[2,3- 443.4f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Example 16 Synthesis of1′-(3-aminopropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of2-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione(3.20 g, 6.80 mmol) in ethanol (70.0 mL) was added hydrazine monohydrate(1.87 g, 37.0 mmol). The mixture was stirred at ambient temperature for4 h. The solvent was removed under reduced pressure and the residue wasre-dissolved in ethyl acetate. The solution was washed with sodiumbicarbonate and brine solution, dried over MgSO₄ and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue wascrystallized from hexane to yield the title compound (2.50 g) in 75%yield: ¹H NMR (300 MHz, CDCl₃) δ 7.31-7.24 (m, 1H), 7.16-7.14 (m, 1H),7.06-7.01 (m, 1H), 6.94-6.91 (m, 1H), 6.48 (s, 1H), 6.10 (s, 1H), 5.82(m, 2H), 4.90-4.87 (m, 1H), 4.61 (d, 1H), 3.98-3.71 (m, 2H), 2.77-2.73(m, 2H), 1.97 (br, 2H), 1.84-1.81 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 155.9, 148.9, 142.3, 142.2, 132.4, 129.0, 124.0, 123.4, 119.4,108.7, 103.0, 101.5, 93.6, 80.5, 58.2, 38.8, 37.5, 30.6; MS (ES+) m/z339.3 (M+1).

Example 17 Synthesis of3-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]thiophene-2-carboxamide

To a solution of1′-(3-aminopropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.05 g, 0.13 mmol) in dichloromethane (4.00 mL) was added triethylamine(0.03 g, 0.26 mmol) and 3-chlorothiophene-2-carbonyl chloride (0.02 g,0.12 mmol) at 0° C. The mixture was stirred for 2 h, washed with 15% HClsolution and water. The organic layer was dried over MgSO₄ and filtered.The filtrate was concentrated in vacuo to dryness. The residue wasdissolved in ethyl acetate, and the product was precipitated with theaddition of hexane. The white solid was collected by filtration anddried in vacuo to yield the title compound (0.04 g) in 67% yield: ¹H NMR(300 MHz, CDCl₃) δ 7.60 (t, 1H), 7.41 (d, 1H), 7.33-7.27- (m, 1H), 7.17(d, 1H), 7.08-7.03- (m, 1H), 6.93 (t, 1H), 6.49 (s, 1H), 6.11 (s, 1H),5.95 (m, 2H), 4.90 (d, 1H), 4.65 (d, 1H), 3.96-3.79- (m, 2H), 3.53-3.36-(m, 2H), 2.04-1.93- (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.3, 160.6,156.0, 149.0, 142.4, 141.8, 132.5, 129.4, 129.2, 129.1, 124.2, 123.7,123.6, 119.2, 108.5, 102.9, 101.6, 93.7, 80.5, 58.3, 37.4, 36.5, 27.3;MS (ES+) m/z 483 (M+1).

Example 17.1

The compounds listed in the following table were synthesized using thesimilar procedure as described in EXAMPLE 17. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound Number Name MS (m/z, M + 1) 680N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 407.31′(2′H)-yl)propyl]cyclopropanecarboxamide 681N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 421.31′(2′H)-yl)propyl]cyclobutanecarboxamide 6822-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 478.37,3′-indol]-1′(2′H)-yl)propyl]nicotinamide 683N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 435.31′(2′H)-yl)propyl]cyclopentanecarboxamide 6842,2-dimethyl-N-[3-(2′-oxospiro[furo[2,3- 423.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]propanamide 6852-(4-methoxyphenyl)-N-[3-(2′-oxospiro[furo[2,3- 487.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 6864-tert-butyl-N-[3-(2′-oxospiro[furo[2,3- 499.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 6873,3-dimethyl-N-[3-(2′-oxospiro[furo[2,3- 437.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]butanamide 688N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 519.31′(2′H)-yl)propyl]biphenyl-4-carboxamide 6893-methyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 497.27,3′-indol]-1′(2′H)-yl)propyl]-1-benzofuran-2- carboxamide 6902-(benzyloxy)-N-[3-(2′-oxospiro[furo[2,3- 487.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 691N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 433.31′(2′H)-yl)propyl]-2-furamide 692N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 487.31′(2′H)-yl)propyl]-1,3-benzodioxole-5-carboxamide 693N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 494.31′(2′H)-yl)propyl]quinoline-2-carboxamide 694N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 457.41′(2′H)-yl)propyl]-2-phenylacetamide 695N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 450.31′(2′H)-yl)propyl]piperidine-1-carboxamide 6962-methoxy-N-[3-(2′-oxospiro[furo[2,3- 411.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 6974-(dimethylamino)-N-[3-(2′-oxospiro[furo[2,3- 486.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 6984-ethoxy-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 487.37,3′-indol]-1′(2′H)-yl)propyl]benzamide 6992-methyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 423.37,3′-indol]-1′(2′H)-yl)propyl]butanamide 700N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 473.21′(2′H)-yl)propyl]-2-phenoxyacetamide 701N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 495.01′(2′H)-yl)propyl]quinoxaline-2-carboxamide 702N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 449.31′(2′H)-yl)propyl]cyclohexanecarboxamide 7034-fluoro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 461.37,3′-indol]-1′(2′H)-yl)propyl]benzamide 7042-ethyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 437.37,3′-indol]-1′(2′H)-yl)propyl]butanamide 7052-(4-fluorophenyl)-N-[3-(2′-oxospiro[furo[2,3- 475.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 7066-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 478.07,3′-indol]-1′(2′H)-yl)propyl]nicotinamide 7072-fluoro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 461.47,3′-indol]-1′(2′H)-yl)propyl]benzamide 708N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 482.81′(2′H)-yl)propyl]-2- phenylcyclopropanecarboxamide 7094-methyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 457.77,3′-indol]-1′(2′H)-yl)propyl]benzamide 7101-(4-fluorophenyl)-5-methyl-N-[3-(2′-oxospiro[furo[2,3- 541.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-1H-pyrazole-4-carboxamide 711N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 483.11′(2′H)-yl)propyl]-1-benzofuran-5-carboxamide 712N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 485.41′(2′H)-yl)propyl]-2,1,3-benzoxadiazole-5- carboxamide 7132,4-dichloro-N-[3-(2′-oxospiro[furo[2,3- 513.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 7141-methyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 498.47,3′-indol]-1′(2′H)-yl)propyl]-1H-1,2,3-benzotriazole- 5-carboxamide 7155-fluoro-2-methyl-N-[3-(2′-oxospiro[furo[2,3- 475.1f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 7162-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 478.17,3′-indol]-1′(2′H)-yl)propyl]isonicotinamide 717N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 501.11′(2′H)-yl)propyl]-2,3-dihydro-1,4-benzodioxine-6- carboxamide 7185-methyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 448.27,3′-indol]-1′(2′H)-yl)propyl]isoxazole-3- carboxamide 719N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 483.11′(2′H)-yl)propyl]-1-benzofuran-2-carboxamide 720N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 499.11′(2′H)-yl)propyl]-1-benzothiophene-2-carboxamide 721N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 501.11′(2′H)-yl)propyl]-2,3-dihydro-1,4-benzodioxine-2- carboxamide 722N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 509.11′(2′H)-yl)propyl]-4-(1H-pyrazol-1-yl)benzamide 7231,3-dimethyl-N-[3-(2′-oxospiro[furo[2,3- 461.2f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-1H-pyrazole-5-carboxamide 7244-methyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 514.27,3′-indol]-1′(2′H)-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide 725N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 495.21′(2′H)-yl)propyl]quinoxaline-6-carboxamide 726N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 485.21′(2′H)-yl)propyl]-2,3-dihydro-1-benzofuran-2- carboxamide 727N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 499.11′(2′H)-yl)propyl]-2,3-dihydro-1-benzothiophene-5- carboxamide 728N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 526.91′(2′H)-yl)propyl]-2-(trifluoromethoxy)benzamide 729N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 445.21′(2′H)-yl)propyl]pentanamide 730N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 473.21′(2′H)-yl)propyl]heptanamide 7313-cyclopentyl-N-[3-(2′-oxospiro[furo[2,3- 463.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]propanamide 7329-oxo-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 545.0indol]-1′(2′H)-yl)propyl]-9H-fluorene-4-carboxamide 733N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 511.41′(2′H)-yl)propyl]-4-(trifluoromethyl)benzamide 7342,5-difluoro-N-[3-(2′-oxospiro[furo[2,3- 479.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 7352,5-dimethyl-N-[3-(2′-oxospiro[furo[2,3- 461.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-3- furamide 736N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 523.31′(2′H)-yl)propyl]-4-phenoxybutanamide 7374-fluoro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 529.07,3′-indol]-1′(2′H)-yl)propyl]-2- (trifluoromethyl)benzamide 738N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 463.31′(2′H)-yl)propyl]-2-(2-thienyl)acetamide 7392-chloro-5-fluoro-N-[3-(2′-oxospiro[furo[2,3- 495.0f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 740N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 493.01′(2′H)-yl)propyl]-2-naphthamide 7412-(4-chlorophenoxy)-N-[3-(2′-oxospiro[furo[2,3- 507.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 7422,4-dimethoxy-N-[3-(2′-oxospiro[furo[2,3- 503.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 7432-nitro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 488.47,3′-indol]-1′(2′H)-yl)propyl]benzamide 7442-(4-chlorophenyl)-3-methyl-N-[3-(2′-oxospiro[furo[2,3- 533.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]butanamide 7454-amino-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 458.47,3′-indol]-1′(2′H)-yl)propyl]benzamide 7463,4-dimethoxy-N-[3-(2′-oxospiro[furo[2,3- 503.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 747N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 558.41′(2′H)-yl)propyl]-5H-dibenzo[b,f]azepine-5- carboxamide 748N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 501.51′(2′H)-yl)propyl]adamantane-1-carboxamide 7492-[(2-isopropyl-5-methylcyclohexyl)oxy]-N-[3-(2′- 535.5oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]acetamide 750N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 579.31′(2′H)-yl)propyl]-3,5-bis(trifluoromethyl)benzamide 7512-(2,5-dimethoxyphenyl)-N-[3-(2′-oxospiro[furo[2,3- 517.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 7522-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 477.37,3′-indol]-1′(2′H)-yl)propyl]benzamide 7533-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 477.37,3′-indol]-1′(2′H)-yl)propyl]benzamide 7544-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 477.37,3′-indol]-1′(2′H)-yl)propyl]benzamide 755N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 437.41′(2′H)-yl)propyl]hexanamide 7562,6-difluoro-N-[3-(2′-oxospiro[furo[2,3- 479.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 7572-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 415.37,3′-indol]-1′(2′H)-yl)propyl]acetamide 758N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 579.41′(2′H)-yl)propyl]-2,5-bis(trifluoromethyl)benzamide 759N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 436.41′(2′H)-yl)propyl]pyrrolidine-1-carboxamide 7602-bromo-2,2-difluoro-N-[3-(2′-oxospiro[furo[2,3- 497.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 7612,3,5-trifluoro-N-[3-(2′-oxospiro[furo[2,3- 497.3f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]benzamide 7625-fluoro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 529.47,3′-indol]-1′(2′H)-yl)propyl]-2- (trifluoromethyl)benzamide 7635-chloro-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 545.37,3′-indol]-1′(2′H)-yl)propyl]-2- (trifluoromethyl)benzamide 764N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 449.31′(2′H)-yl)propyl]thiophene-2-carboxamide 765N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 452.41′(2′H)-yl)propyl]morpholine-4-carboxamide 7662-(1-naphthyl)-N-[3-(2′-oxospiro[furo[2,3- 507.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]acetamide 7672-methyl-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 409.47,3′-indol]-1′(2′H)-yl)propyl]propanamide 768N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 451.41′(2′H)-yl)propyl]-N-propionylpropanamide 769N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 513.31′(2′H)-yl)propyl]-4-pentylbenzamide 7704,7,7-trimethyl-3-oxo-N-[3-(2′-oxospiro[furo[2,3- 519.4f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-2-oxabicyclo[2.2.1]heptane-1-carboxamide 7712-bromo-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 523.27,3′-indol]-1′(2′H)-yl)propyl]benzamide 7723-cyano-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 468.37,3′-indol]-1′(2′H)-yl)propyl]benzamide 7734-cyano-N-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 468.37,3′-indol]-1′(2′H)-yl)propyl]benzamide

Example 18 Synthesis of1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a suspension of2-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]-1H-isoindole-1,3(2H)-dione(20.0 g, 44.0 mmol) in methanol (400 mL) was added hydrazine (8.00 mL).The mixture was stirred at ambient temperature for 48 h and filtered.The filtrate was concentrated in vacuo to dryness. The residue wassubjected to flash chromatography eluting with ethylacetate/methanol/ammonia (10/1/0.2) to afford the crude product whichwas recrystalized from ethyl acetate to yield the title compound (8.0 g)in 56% yield as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.34 (m, 1H),7.17 (dd, 1H), 7.06 (dd, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.18 (s, 1H),5.89-5.82- (ABq, 2H), 4.93 (d, 1H), 4.66 (d, 1H), 3.95-3.74- (m, 2H),3.06 (t, 2H), 1.59-1.35- (br, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.0,155.9, 148.8, 142.3, 132.4, 128.9, 124.0, 123.4, 119.5, 108.6, 103.1,101.5, 93.6, 80.5, 58.2, 43.4, 39.8; MS (ES+) m/z 325 (M+1), 308 (M−16).

Example 19 Synthesis of1-(4-fluorophenyl)-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea

To a mixture of1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.15 mmol) and triethylamine (0.01 mmol) in anhydrous dichloromethanewas added 1-fluoro-4-isocyanatobenzene (0.14 mmol) at ambienttemperature. The mixture was stirred for 16 h, diluted with ofdichloromethane (5.00 mL), washed with 10% HCl solution and brine, driedover Na₂SO₄ and filtered. The filtrate was concentrated in vacuo todryness to give the title compound (0.05 g) in 82% yield: ¹H NMR (300MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.35-7.25 (m, 3H), 7.19 (d, 1H), 7.11 (d,1H), 7.06-6.91 (m, 3H), 6.67 (s, 1H), 6.52 (t, 1H), 5.94-5.84 (ABq, 2H),4.74 (d, 1H), 4.61 (d, 1H), 3.91-3.69 (m, 2H), 3.49-3.34 (m, 2H); MS(ES+) m/z 462 (M+1), 484 (M+23).

Example 19.1

The compounds listed in the following table were synthesized using thesimilar procedure as described in EXAMPLE 19. As previously noted, thecompound numbers listed below do not correspond to the compound numbersprovided in the general Reaction Schemes above.

Compound Number Name MS (m/z, M + 1) 7741-benzyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 4587,3′-indol]-1′(2′H)-yl)ethyl]urea 7751-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 536indol]-1′(2′H)-yl)ethyl]-3-(4-phenoxyphenyl)urea 7761-butyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 4247,3′-indol]-1′(2′H)-yl)ethyl]urea 7771-cyclohexyl-3-[2-(2′-oxospiro[furo[2,3- 450f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7781-ethyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 3967,3′-indol]-1′(2′H)-yl)ethyl]urea 7791-isopropyl-3-[2-(2′-oxospiro[furo[2,3- 410f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7801-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 410indol]-1′(2′H)-yl)ethyl]-3-propylurea 7811-tert-butyl-3-[2-(2′-oxospiro[furo[2,3- 424f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7821-cyclopentyl-3-[2-(2′-oxospiro[furo[2,3- 436f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7831-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 438indol]-1′(2′H)-yl)ethyl]-3-pentylurea 7841-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 444indol]-1′(2′H)-yl)ethyl]-3-phenylurea 7851-(2-furylmethyl)-3-[2-(2′-oxospiro[furo[2,3- 448f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7861-hexyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 4527,3′-indol]-1′(2′H)-yl)ethyl]urea 787 ethylN-({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 4547,3′-indol]-1′(2′H)-yl)ethyl]amino}carbonyl)glycinate 7881-(3-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 458f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7891-(4-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 458f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 790 ethylN-({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 4687,3′-indol]-1′(2′H)-yl)ethyl]amino}carbonyl)-beta- alaninate 7911-(4-cyanophenyl)-3-[2-(2′-oxospiro[furo[2,3- 469f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 792N-({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 472indol]-1′(2′H)-yl)ethyl]amino}carbonyl)benzamide 7931-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 473indol]-1′(2′H)-yl)ethyl]-3-(2-phenylethyl)urea 7941-(4-methylbenzyl)-3-[2-(2′-oxospiro[furo[2,3- 472f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7951-(2-methylbenzyl)-3-[2-(2′-oxospiro[furo[2,3- 472f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7961-(4-ethylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 472f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7971-(3-methoxyphenyl)-3-[2-(2′-oxospiro[furo[2,3- 474f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7981-(2-fluoro-5-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 476f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 7991-(3-fluoro-4-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 476f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8001-(4-chlorophenyl)-3-[2-(2′-oxospiro[furo[2,3- 479f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8012-[({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 480indol]-1′(2′H)-yl)ethyl]amino}carbonyl)amino]ethyl 2-methylacrylate 8021-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 480indol]-1′(2′H)-yl)ethyl]-3-(1,1,3,3- tetramethylbutyl)urea 803 ethyl4-[({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 4827,3′-indol]-1′(2′H)- yl)ethyl]amino}carbonyl)amino]butanoate 8041-[4-(cyanomethyl)phenyl]-3-[2-(2′-oxospiro[furo[2,3- 483f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8051-(2,3-dihydro-1H-inden-5-yl)-3-[2-(2′-oxospiro[furo[2,3- 483f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8061-(3-acetylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 484f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8071-(4-acetylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 486f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8081-(4-isopropylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 486f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8091-(2-methoxybenzyl)-3-[2-(2′-oxospiro[furo[2,3- 486f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8101-(4-methoxybenzyl)-3-[2-(2′-oxospiro[furo[2,3- 488f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8111-(4-methoxy-2-methylphenyl)-3-[2-(2′- 4882oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea812 1-(4-chloro-2-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 488f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8131-(3-chloro-4-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 493f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8141-(3-chloro-2-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 493f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8151-(5-chloro-2-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 493f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8161-(2-chlorobenzyl)-3-[2-(2′-oxospiro[furo[2,3- 493f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8171-(1-naphthyl)-3-[2-(2′-oxospiro[furo[2,3- 493f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8181-(2-naphthyl)-3-[2-(2′-oxospiro[furo[2,3- 494f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8191-(3-chloro-2-fluorophenyl)-3-[2-(2′-oxospiro[furo[2,3- 494f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8201-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 497indol]-1′(2′H)-yl)ethyl]-3-(5,6,7,8- tetrahydronaphthalen-1-yl)urea 8211-(4-tert-butylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 498f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8221-(4-butylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 500f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8231-[2-(4-ethylphenyl)ethyl]-3-[2-(2′-oxospiro[furo[2,3- 500f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8241-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[2-(2′- 500oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea825 methyl 4-[({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 5027,3′-indol]-1′(2′H)- yl)ethyl]amino}carbonyl)amino]benzoate 8261-(2-ethoxybenzyl)-3-[2-(2′-oxospiro[furo[2,3- 502f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8271-(3,4-dimethoxyphenyl)-3-[2-(2′-oxospiro[furo[2,3- 502f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8281-(3,5-dimethoxyphenyl)-3-[2-(2′-oxospiro[furo[2,3- 504f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8291-(3-chloro-4-methoxyphenyl)-3-[2-(2′- 504oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea830 1-[4-(difluoromethoxy)phenyl]-3-[2-(2′-oxospiro[furo[2,3- 509f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8311-[2-(difluoromethoxy)phenyl]-3-[2-(2′-oxospiro[furo[2,3- 510f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8321-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 510indol]-1′(2′H)-yl)ethyl]-3-[3- (trifluoromethyl)phenyl]urea 8331-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 512indol]-1′(2′H)-yl)ethyl]-3-[2- (trifluoromethyl)phenyl]urea 8341-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 512indol]-1′(2′H)-yl)ethyl]-3-[4- (trifluoromethyl)phenyl]urea 8351-(3,4-dichlorophenyl)-3-[2-(2′-oxospiro[furo[2,3- 512f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8361-(2,3-dichlorophenyl)-3-[2-(2′-oxospiro[furo[2,3- 513f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8371-(3,5-dichlorophenyl)-3-[2-(2′-oxospiro[furo[2,3- 513f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 838 ethyl4-[({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 5137,3′-indol]-1′(2′H)- yl)ethyl]amino}carbonyl)amino]benzoate 839 ethyl2-[({[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- 5167,3′-indol]-1′(2′H)- yl)ethyl]amino}carbonyl)amino]benzoate 8401-[2-(1,3-benzodioxol-5-yl)ethyl]-3-[2-(2′- 516oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea841 methyl 2-methyl-3-[({[2-(2′-oxospiro[furo[2,3- 516f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]amino}carbonyl)amino]benzoate 8421-(4-butoxyphenyl)-3-[2-(2′-oxospiro[furo[2,3- 516f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8431-(2-methoxy-4-nitrophenyl)-3-[2-(2′-oxospiro[furo[2,3- 516f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8441-biphenyl-2-yl-3-[2-(2′-oxospiro[furo[2,3- 519f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8451-[4-methyl-3-(trifluoromethyl)phenyl]-3-[2-(2′- 520oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea846 1-(2,4-dichlorobenzyl)-3-[2-(2′-oxospiro[furo[2,3- 526f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8471-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 527indol]-1′(2′H)-yl)ethyl]-3-[2- (trifluoromethoxy)phenyl]urea 8481-[4-fluoro-2-(trifluoromethyl)phenyl]-3-[2-(2′- 528oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea849 1-(5-tert-butyl-2-methoxyphenyl)-3-[2-(2′- 530oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea850 1-[2-(3,5-dimethoxyphenyl)ethyl]-3-[2-(2′- 530oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea851 1-(9H-fluoren-2-yl)-3-[2-(2′-oxospiro[furo[2,3- 532f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8521-(9H-fluoren-9-yl)-3-[2-(2′-oxospiro[furo[2,3- 532f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8531-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 532indol]-1′(2′H)-yl)ethyl]-3-(3,4,5- trimethoxyphenyl)urea 8541-(diphenylmethyl)-3-[2-(2′-oxospiro[furo[2,3- 534f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8551-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 534indol]-1′(2′H)-yl)ethyl]-3-(2-phenoxyphenyl)urea 8561-(2-biphenyl-4-ylethyl)-3-[2-(2′-oxospiro[furo[2,3- 536f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8571-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- 548indol]-1′(2′H)-yl)ethyl]-3-(3,4,5- trimethoxybenzyl)urea 8581-(2-nitrophenyl)-3-[2-(2′-oxospiro[furo[2,3- 548f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8591-(1,3-benzodioxol-5-yl)-3-[2-(2′-oxospiro[furo[2,3- 489f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8601-[4-(dimethylamino)phenyl]-3-[2-(2′-oxospiro[furo[2,3- 488f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8611-(2-fluorobenzyl)-3-[2-(2′-oxospiro[furo[2,3- 487f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8621-(4-fluoro-3-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 476f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8631-(3-fluorobenzyl)-3-[2-(2′-oxospiro[furo[2,3- 476f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8641-(cyclohexylmethyl)-3-[2-(2′-oxospiro[furo[2,3- 476f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8651-(2-methylphenyl)-3-[2-(2′-oxospiro[furo[2,3- 464f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]urea 8661-[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]-3-[2-(2′- 458oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 1′(2′H)-yl)ethyl]urea

Example 20 Synthesis of1′-pentyl-7H-spiro[furo[3,4-f][1,3]benzodioxole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1, and makingnon-critical variations using3-hydroxy-3-[6-(hydroxymethyl)-1,3-benzodioxol-5-yl]-1-pentyl-1,3-dihydro-2H-indol-2-oneto replace1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one,the title compound was obtained (45%) as a colorless solid: mp 113-115°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.24-7.33 (m, 1H), 7.12 (dd, 1H), 7.01 (t,1H), 6.87 (d, 1H), 6.74 (s, 1H), 6.15 (s, 1H), 5.92 (dd, 2H), 5.48 (d,1H), 5.27 (d, 1H), 3.76-3.56 (m, 2H), 1.71-1.64- (m, 2H), 1.37-1.27- (m,4H), 0.89-0.84 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 175.9, 148.7, 148.1,143.6, 133.7, 132.1, 130.3, 129.8, 125.3, 125.0, 123.1, 113.5, 109.1,108.7, 101.9, 101.7, 88.7, 74.4, 40.0, 29.7, 29.0, 25.3, 13.3; MS (ES+)m/z 352.1 (M+1).

Example 21 Synthesis of1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione

To a solution of[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]aceticacid (0.28 g, 0.73 mmol) was added one drop of DMF and oxalyl chloride(0.32 mL, 3.7 mmol) in toluene (10 mL). The mixture was stirred atambient temperature overnight and concentrated under vacuum to drynessto afford a brown oil. This substance was dissolved in dichloromethane(15.0 mL) followed by the addition of tin (IV) chloride (0.07 mL, 0.57mmol) at 0° C. The mixture was stirred at ambient temperature overnightand quenched with ice water. The mixture was poured into water (100 mL),and the mixture was extracted with dichloromethane (150 mL). The organiclayer was washed with water, dried over sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto flash column chromatography to afford the title compound (0.09 g,67%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.31 (td, 1H), 7.14 (s,1H), 7.02 (td, 1H), 6.97-6.92 (m, 2H), 6.22 (s, 1H), 6.03-5.98 (m, 2H),3.87-3.63 (m, 2H), 3.17 (d, 1H), 2.85 (d, 1H), 1.79-1.66 (m, 2H),1.41-1.30 (m, 4H), 0.88 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 201.4, 177.5,154.8, 151.8, 149.6, 143.1, 132.5, 131.6, 128.9, 123.4, 123.2, 108.9,103.5, 102.6, 102.5, 53.8, 47.7, 40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+),m/z 386.1 (M+23), 364.1 (M+1).

Example 22 Synthesis of1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dione

Following the procedure as described in EXAMPLE 21, and makingnon-critical variations using3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoicacid to replace[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]aceticacid, the title compound was obtained (32%) as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 7.57 (s, 1H), 7.37-7.28 (m, 1H), 7.08-7.03 (m, 2H),6.95 (d, 1H), 6.02 (s, 1H), 5.95-5.91 (m, 2H), 3.73 (t, 2H), 3.37-3.24(m, 1H), 2.79-2.67(m, 1H), 2.41-2.32 (m, 2H), 1.76-1.64 (m, 2H),1.38-1.28 (m, 4H), 0.87 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 195.4, 177.4,152.3, 148.0, 142.7, 138.9, 133.6, 128.8, 128.4, 124.1, 122.9, 108.9,106.9, 106.6, 101.9, 51.7, 40.2, 33.1, 32.8, 29.0, 27.1, 22.3, 14.0; MS(ES+) m/z 400.1 (M+23), 378.1 (M+1).

Example 23 Synthesis of1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one

A mixture of1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione(0.04 g, 0.11 mmol), triethylsilane (1.50 mL) and trifluroacetic acid(2.00 mL, excess) was stirred at ambient temperature overnight. Themixture was concentrated in vacuo to dryness. The residue was subjectedto flash column chromatography to afford the title compound (0.02 g,47%) as an oil: ¹H NMR (300 MHz, CDCl₃) δ 7.25 (td, 1H), 7.06-6.95 (m,2H), 6.88 (d, 1H), 6.77 (s, 1H), 6.05 (s, 1H), 5.88-5.82 (m, 2H),3.81-3.60 (m, 2H), 3.37-3.24 (m, 1H), 3.13-3.01 (m, 1H), 2.70-2.59 (m,1H), 2.44-2.32 (m, 1H), 1.76-1.64 (m, 2H), 1.39-1.28 (m, 4H), 0.88 (t,3H); ¹³C NMR (75 MHz, CDCl₃) δ 179.5, 147.9, 147.0, 142.9, 138.2, 136.7,134.7, 128.1, 123.5, 122.6, 108.3, 105.3, 103.6, 101.2, 59.9, 40.0,38.3, 31.6, 29.0, 27.1, 22.6, 14.0; MS (ES+) m/z 372.1 (M+23), 350.1(M+1).

Example 24 Synthesis of1-pentyl-7′,8′-dihydro-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxol]-2(1H)-one

Following the procedure as described in EXAMPLE 23, and makingnon-critical variations using1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dioneto replace1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione,the title compound was obtained (69%) as an oil: ¹H NMR (300 MHz, CDCl₃)δ 7.25 (td, 1H), 7.08-6.94 (m, 2H), 6.90 (d, 1H), 6.60 (s, 1H), 5.89 (s,1H), 5.81-5.76 (m, 2H), 3.81-3.66 (m, 2H), 2.96-2.77 (m, 2H), 2.38-2.24(m, 1H), 2.17-2.06 (m, 1H), 2.02-1.83 (m, 2H), 1.78-1.65 (m, 2H),1.42-1.29 (m, 4H), 0.89 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 180.3, 146.7,146.1, 142.4, 137.3, 131.6, 127.8, 127.8, 124.1, 122.5, 109.0, 108.3,107.3, 100.7, 52.0, 40.0, 34.0, 29.4, 29.1, 27.1, 22.4, 18.8, 14.0; MS(ES+) m/z 364.1 (M+1).

Example 25 Synthesis of8′,8′-difluoro-1-pentyl-7′,8′-dihydro-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxol]-2(1H)-one

A mixture of1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dione(0.02 g, 0.05 mmol), bis(2-methoxyethyl)aminosulfur trifluoride (0.50mL) and one drop of ethanol was stirred at 85° C. for 72 hours in aTeflon bottle and quenched by slowly addition of water. The mixture waspoured into water (100 mL) and extracted with ethyl acetate (100 mL).The organic layer was washed with water, dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas subjected to flash column chromatography to afford the titlecompound (0.01 g, 47%) as an oil: ¹H NMR (300 MHz, CDCl₃) δ 7.57 (s,1H), 7.38-7.28 (m, 1H), 7.09-7.01 (m, 2H), 6.95 (d, 1H), 6.03 (s, 1H),5.96-5.90 (m, 2H), 3.73 (t, 2H), 3.38-3.24 (m, 1H), 2.79-2.67 (m, 1H),2.41-2.32 (m, 2H), 1.77-1.63 (m, 2H), 1.39-1.28 (m, 4H), 0.90 (t, 3H);¹³C NMR (75 MHz, CDCl₃) δ 195.4, 177.4, 152.3, 148.0, 142.7, 138.9,133.6, 128.8, 128.4, 124.1, 122.9, 108.9, 106.9, 106.6, 101.9, 51.7,40.2, 33.1, 32.8, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 422.2 (M+23),380.2 (M+1).

Example 26 Synthesis of7-hydroxy-1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one

To a solution of1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dione(0.20 g, 0.55 mmol) in methanol (10.0 mL) was added sodium borohydride(0.03 g, 0.83 mmol). The reaction mixture was stirred at ambienttemperature for 2 h and poured into of water (100 mL) and extracted withethyl acetate (100 mL). The organic layer was washed with water, driedover sodium sulfate and filtered. The filtrate was concentrated in vacuoto dryness. The residue was subjected to flash column chromatography toafford the title compound (0.18 g, 90%) as an oil: ¹H NMR (300 MHz,CDCl₃) δ 7.36-7.29 (m, 1H), 7.11-6.99 (m, 3H), 6.93 (d, 1H), 5.98 (s,1H), 5.94-5.87 (m, 2H), 5.16 (d, 1H), 3.80-3.61 (m, 2H), 2.69 (br, 1H),2.39 (d, 1H), 1.75-1.62 (m, 2H), 1.38-1.22 (m, 4H), 0.87 (t, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 180.5, 148.9, 148.5, 143.7, 140.5, 136.9, 132.1,128.7, 123.7, 123.3, 108.8, 105.7, 103.2, 101.5, 74.8, 59.6, 40.4, 28.9,27.0, 22.3, 14.0; MS (ES+) m/z 388.4 (M+23).

Example 27 Synthesis of7-methoxy-1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one

To a solution of7-hydroxy-1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one(0.05 g, 0.14 mmol) in THF (10.0 mL) was added sodium hydride (0.01 mg,0.21 mmol) at 0° C. The reaction mixture was stirred for half an hourfollowed by the addition of iodomethane (0.50 mL). The mixture wasstirred at ambient temperature for two hours, then poured into water(100 mL), and extracted with ethyl acetate (100 mL). The organic layerwas washed with water, dried over sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto flash column chromatography to afford the title compound (0.03 g,57%) as an oil: ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.18 (m, 1H), 6.98-6.82(m, 4H), 6.10 (s, 1H), 5.88 (s, 2H), 5.26 t, 1H), 3.88-3.63 (m, 2H),3.45 (s, 3H), 2.71-2.54 (m, 2H), 1.80-1.65 (m, 2H), 1.45-1.29 (m, 4H),0.90 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.3, 148.9, 148.4, 142.4,136.8, 136.6, 135.1, 128.1, 123.1, 122.6, 108.5, 105.0, 103.2, 101.5,82.7, 57.9, 55.6, 43.4, 40.3, 29.1, 27.2, 22.4, 14.0: MS (ES+) m/z 402.4(M+23).

Example 28 Synthesis of1′-pentyl-6,7-dihydro-5H-spiro[1,3-dioxolo[4,5-g]isoquinoline-8,3′-indole]-2′,5(1′H)-dione

A mixture of1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione(0.10 g, 0.28 mmol), sodium azide (0.09 g, 1.40 mmol) andtrifluoroacetic acid (2.00 mL) was stirred at 50° C. overnight. Themixture was poured into water (100 mL) and extracted with ethyl acetate(100 mL). The organic layer was washed with water, dried over sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to flash column chromatography to afford thetitle compound (0.08 g, 74%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.60 (s, 1H), 7.30 (td, 1H), 7.20 (dd, 1H), 6.98 (td, 1H), 6.93 (d, 1H),6.32 (br, 1H), 6.21 (s, 1H), 5.97-5.92 (m, 2H), 4.02 (dd, 1H), 3.87-3.70(m, 2H), 3.47 (dd, 1H), 1.80-1.66 (m, 2H), 1.42-4.30 (m, 4H), 0.90 (t,3H); ¹³C NMR (75 MHz, CDCl₃) δ 175.8, 165.2, 151.6, 147.9, 141.7, 134.3,130.9, 129.0, 124.5, 123.2, 122.9, 109.0, 108.5, 105.4, 101.9, 51.9,48.2, 40.4, 29.1, 27.1, 22.3, 14.0; MS (ES+) m/z 379.3 (M+1).

Example 29 Synthesis of2′-oxo-1′-pentyl-N-pyridin-2-yl-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-4′-carboxamide

A mixture of4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.28 g, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 g,10 mole %), triethylamine (0.33 g, 0.50 mL, 3.25 mmol) and2-aminopyridine (0.12 g, 1.30 mmol) in N,N-dimethylformamide (5.00 mL)was subjected to carbon monoxide (40 Psi). The reaction mixture washeated at 80° C. for 16 h. After cooling down to ambient temperature,the reaction mixture was diluted with ethyl acetate (20.0 mL), washedwith water (3×20.0 mL), brine (2×20.0 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to column chromatography to give the titlecompound (0.04 g, 14%) as a solid: ¹H NMR (300 MHz, CDCl₃) δ 8.52 (d,1H), 7.87 (br, 1H), 7.69-7.62 (m, 3H), 7.53-7.51 (m, 1H), 7.47-7.38 (m,3H), 7.04-6.98 (m, 1H), 5.79 (d, 2H), 4.97 (ABq, 2H), 3.84-3.66 (m, 2H),1.77-1.67 (m, 2H), 1.38-1.33 (m, 4H), 0.90 (t, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 177.5, 158.2, 156.7, 149.2, 143.5, 142.1, 132.2, 132.0, 131.9,131.8, 129.6, 128.6, 128.4, 121.8, 118.2, 110.7, 102.0, 101.4, 93.9,79.5, 77.2, 58.5, 40.6, 29.0, 27.0, 22.3, 14.0; MS (ES+) m/z 473.2(M+2).

Example 29.1 Synthesis ofN-(3-methoxyphenyl)-2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 29, and making non-criticalvariations using 3-methoxyaniline to replace 2-aminopyridine, the titlecompound was obtained (20%) as a colorless solid: mp 173-175° C.; ¹H NMR(300 MHz, CDCl₃) δ 7.42 (t, 1H), 7.30-7.27 (m, 1H), 7.14 (t, 1H),7.04-6.97 (m, 2H), 7.23 (s, 1H), 6.74-6.62 (m, 2H), 6.31 (s, 1H), 6.16(s, 1H), 5.83 (dd, 2H), 4.87-5.01 (m, 2H), 3.91-3.63 (m, 5H), 1.73-1.78(m, 2H), 1.37-1.32 (m, 4H), 0.93-0.86 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 165.1, 159.9, 149.3, 143.6, 143.5, 142.1, 138.1, 134.5, 129.7,129.5, 127.9, 122.4, 118.3, 112.2, 110.7, 110.5, 105.6, 101.9, 101.6,94.3, 79.2, 58.3, 55.3, 40.5, 28.9, 26.9, 22.3, 13.9; MS (ES+) m/z 501.5(M+1).

Example 30 Synthesis of2′-oxo-1′-pentyl-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-4′-carbonitrile

A mixture of4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.10 g, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.21 g,0.23 mmol) and 2-(di-tert-butylphosphino)biphenyl (0.07, 0.23 mmol),tributyltin cyanide (0.07 g, 0.23 mmol) and potassium cyanide (0.02 g,0.23 mmol) was purged with nitrogen and anhydrous acetonitrile (10.0 mL)was added. The reaction mixture was refluxed for 16 h. After coolingdown to ambient temperature, the reaction mixture was diluted with ethylacetate (20.0 mL), washed with water (20.0 mL), brine (20.0 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The brown residue was subjected tocolumn chromatography eluting with ethyl acetate/hexane (65%) to givethe title compound (0.03 g, 33%) which was recrystallized from ether toget a colorless solid: mp 128-129° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.10(s, 1H), 7.42-7.37 (m, 1H), 7.29-7.27 (m, 1H), 7.09 (d, 1H), 6.53 (s,1H), 6.03 (s, 1H), 5.87 (dd, 2H), 4.91 (q, 2H), 3.86-3.63 (m, 2H),1.74-1.62 (m, 2H), 1.43-1.26 (m, 4H), 0.89 (t, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 176.5, 157.1, 149.5, 143.5, 142.4, 135.4, 129.7, 128.3, 126.4,116.3, 114.8, 112.3, 108.8, 102.2, 93.7, 78.7, 58.3, 40.6, 28.9, 26.7,22.2, 13.9; MS (ES+) m/z 377.5 (M+1).

Example 31 Synthesis of1′-hexylspiro[1,3-dioxolo[4,5-g]chromene-8,3′-indole]-2′,6(1′H,7H)-dione

To a solution of2-(1-hexyl-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-2-oxoindolin-3-yl)acetate(0.19 g, 0.43 mmol) in THF:H₂O (2:1) was added lithium hydroxide (0.04g, 0.86 mmol). The mixture was stirred at ambient temperature for 4 hrs.The organic solvent was removed in vacuo and the pH of the aqueousresidue was adjusted to 2 followed by extraction with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness and the residue wassubjected to column chromatography eluting with 25% ethyl acetate/hexaneto yield the title compound (0.09 g, 53%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 7.33 (dt, 1H), 7.14-7.03 (m, 2H), 6.93 (d, 1H), 6.66 (s,1H), 6.06 (s, 1H), 5.88 (dd, 2H), 3.76-3.63 (m, 2H), 2.94 (q, 2H),1.69-1.62 (m, 2H) 1.34-1.22 (m, 6H), 0.83 (t, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 175.9, 165.8, 148.3, 147.2, 144.6, 142.6, 129.9, 129.6, 123.8,123.4, 114.7, 109.2, 105.1, 101.9, 99.8, 49.6, 40.3, 37.2, 31.2, 27.2,26.4, 22.4, 13.9; MS (ES+) m/z 394.5 (M+1).

Example 32 Synthesis of1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.10 g, 0.27 mmol) and palladium/carbon (0.09 g, 0.01 mmol) inmethanol/ethyl acetate (1/1, 4.00 mL) was stirred under hydrogen atatmospheric pressure for 16 h. The solvent was evaporated and the blackresidue was subjected to column chromatography (ethyl acetate/hexane,1/6) to give the title compound (0.08 g, 97%) as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 7.30 (dd, 1H), 7.18 (dd, 1H), 7.20 (d, 1H), 7.02 (dd,1H), 6.96-6.90 (m, 2H), 6.79 (dd, 1H), 6.69 (d, 1H), 4.93 (d, 1H), 4.67(d, 1H), 3.89-3.64 (m, 2H), 1.81-1.66 (m, 2H), 1.44-1.31 (m, 4H), 0.92(t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.2, 160.7, 142.5, 132.8, 129.7,129.0, 128.8, 123.9, 123.3, 123.1, 121.3, 110.4, 108.6, 58.1, 40.4,29.0, 27.2, 22.3,14.0; MS (ES+) m/z 308.5 (M+1).

Example 33 Synthesis of6-anilino-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.08 g,0.19 mmol) in anhydrous toluene (4.00 mL) was added aniline (0.03 g,0.29 mmol), xanthphos (0.02 g, 0.03 mmol) andtris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.02 mmol). Thereaction mixture was refluxed for 16 h, cooled down to ambienttemperature and concentrated in vacuo to dryness. The black residue wassubjected to column chromatography (ethyl acetate/hexane, 1/7) to givethe title compound (0.05 g, 62%) as a yellow oil: ¹H NMR (300 MHz,CDCl₃) δ 7.40-7.25 (m, 6H), 7.18 (d, 1H), 7.12-7.05 (m, 3H), 6.98-6.90(m, 2H), 6.71 (d, 1H), 6.57 (d, 1H), 6.48 (dd, 1H), 4.93 (d, 1H), 4.67(d, 1H), 3.88-3.64 (m, 2H), 1.80-1.65 (m, 2H), 1.45-1.30 (m, 4H), 0.92(t, 3H); MS (ES+) m/z 399.5 (M+1).

Example 34 Synthesis of6-morpholin-4-yl-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(1:1)

Following the procedure as described in EXAMPLE 33, and makingnon-critical variations using morphine to replace aniline, the titlecompound was obtained (42%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ7.32 (d, 1H), 7.15 (d, 1H), 7.05 (dd, 1H), 6.91 (d, 1H), 6.59 (d, 1H),6.50 (d, 1H), 6.35 (dd, 1H), 4.95 (d, 1H), 4.65 (d, 1H), 3.89-3.60 (m,6H), 3.15-3.05 (m, 4H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t,3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 162.2, 153.4, 142.6, 132.9, 128.7,123.9, 123.4, 123.0, 120.1, 108.9, 108.5, 97.9, 80.3, 66.9, 57.7, 49.4,40.3, 29.0, 27.1, 22.4, 14.0; MS (ES+) m/z 393.5 (M+1).

Example 35 Synthesis of6-amino-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A. Synthesis of6-[(diphenylmethylene)amino]-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.10 g,0.26 mmol) in anhydrous toluene (5.00 mL) was added benzophenone imine(0.09 g, 0.52 mmol), sodium t-butoxide (0.03 g, 0.36 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.07 mmol) and(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.12 g, 0.19 mmol).The reaction mixture was refluxed for 16 h, cooled down to ambienttemperature, diluted with dichloromethane (50.0 mL) and filtered througha celite bed. The filtrate was concentrated in vacuo to dryness to givethe title compound which was used in next step without purification.

B. Synthesis of6-amino-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of6-[(diphenylmethylene)amino]-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-onein anhydrous tetrahydrofuran (4.00 mL) was added aqueous 10%hydrochloric acid (2.00 mL). The reaction mixture was stirred for 15min, diluted with aqueous sodium bicarbonate (5.00 mL) and extractedwith ethyl acetate (3×25.0 mL). The combined organic solution was driedover sodium sulfate and filtered. The filtrate was concentrated in vacuoto dryness. The residue was subjected to column chromatography (ethylacetate/hexane, 1/1) to give the title compound (0.02 g, 24% yield) as ayellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.26 (td, 1H), 7.12 (d, 1H), 6.99(dd, 1H), 6.89 (d, 1H), 6.43 (d, 1H), 6.23 (d, 1H), 6.08 (dd, 1H), 4.86(d, 1H), 4.60 (d, 1H), 3.86-3.60 (m, 2H), 1.77-1.65 (m, 2H), 1.41-1.30(m, 4H), 0.89 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 171.2, 162.1,148.7, 142.5, 133.1, 128.6, 127.8, 123.9, 123.7, 123.0, 118.5, 108.5,108.4, 97.2, 80.2, 77.6, 77.4, 77.2, 76.8, 64.0, 60.4, 57.6, 40.3, 29.7,29.0, 27.1, 22.6, 22.4, 22.1, 19.1, 14.2, 14.0, 13.7; MS (ES+) m/z 323.5(M+1).

Example 36 Synthesis of1′-pentyl-6-phenoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.08 g,0.19 mmol) in anhydrous dioxane (4.00 mL) was added copper iodide (0.01g, 0.01 mmol), N,N-dimethyl glycine hydrochloride (0.01 g, 0.01 mmol),cesium carbonate (0.17 g, 0.52 mmol) and phenol (0.03 g, 0.32 mmol). Theresulted mixture was refluxed for 16 h under nitrogen, diluted withdichloromethane (50.0 mL) and filtered through a celite bed. Thefiltrate was concentrated in vacuo to dryness. The residue was subjectedto column chromatography (ethyl acetate/hexane, 1/6) to give the titlecompound (0.07 g, 87%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.36-7.28 (m, 3H), 7.20-7.00 (m, 4H), 6.92 (d, 1H), 6.62 (dd, 1H), 6.58(br, 1H), 6.44 (dd, 1H), 4.95 (d, 1H), 4.71 (d, 1H), 3.92-3.64 (m, 2H),1.70-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H); MS (ES+) m/z 400.5(M+1).

Example 37 Synthesis of1′-pentyl-6-pyridin-3-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.08 g, 0.19 mmol), pyridine-3-boronic acid (0.05 g, 0.41 mmol),palladium acetate (0.002 g, 0.07 mmol), tri-O-tolylphosphine (0.0015 g,0.005 mmol), 2 M sodium carbonate (1.00 mL) and 1,2-dimethoxyethane(9.00 mL) was heated at reflux for 16 hours under N₂. The solvent wasevaporated and the black residue was extracted with ethyl acetate(4×15.0 mL). The combined organics was dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas subjected to column chromatography (ethyl acetate/hexane, 4/1) togive the title compound (0.07 g, 67% yield) as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 8.60 (br, 1H), 7.85 (d, 1H), 7.45-7.24 (m, 3H),7.20-7.10 (m, 2H), 7.12-6.98 (m, 2H), 6.95 (d, 1H), 6.81 (d, 1H), 5.05(d, 1H), 4.78 (d, 1H), 3.89-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34(m, 4H), 0.92 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.9, 161.6, 149.5,147.3, 142.6, 139.9, 136.4, 135.6, 133.4, 130.1, 129.2, 124.9, 121.7,119.5, 110.3, 109.7, 107.7, 80.1, 57.8, 42.3, 28.8, 27.1, 22.3, 14.85;MS (ES+) m/z 385.5 (M+1).

Example 38 Synthesis of1′-pentyl-6-pyridin-4-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 37, and makingnon-critical variations using 4-pyridine boronic acid to replace3-pyridine boronic acid, the title compound was obtained (38%) as whitesolid: mp 107-110° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.64-8.58 (m, 2H),7.45-7.40 (m, 2H), 7.31 (dt, 1H), 7.19-7.13 (m, 2H), 6.93 (d, 1H), 6.79(d, 1H), 4.95 (d, 1H), 4.75 (d, 1H), 3.88-3.64 (m, 2H), 1.80-1.68 (m,2H), 1.43-1.34 (m, 4H), 0.90 (t, 3H); MS (ES+) m/z 385.5 (M+1).

Example 39 Synthesis of6-(methylsulfonyl)-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.60 g, 1.55 mmol), sodium methanesulfinate (0.19 g, 1.86 mmol), copperiodide (0.03 g, 0.16 mmol), and L-proline (0.04 g, 0.31 mmol) indimethyl sulfoxide (3.00 mL) was heated at 100° C. for 2 days under N₂.The reaction mixture was diluted with water (50.0 mL) and extracted withethyl acetate (4×15.0 mL). The combined organics was dried over sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was subjected to column chromatography (ethylacetate/hexane, 2/3) to give the title compound (0.03 g, 46%) as a lightyellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.48 (m, 1H), 7.38 (dt, 1H),7.34 (dt, 1H), 7.13-7.02 (m, 2H), 6.94 (d, 1H), 6.86 (d, 1H), 5.03 (d,1H), 4.78 (d, 1H), 3.87-3.64 (m, 2H), 3.02 (s, 3H), 1.79-1.68 (m, 2H),1.41-1.32 (m, 4H), 0.90 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.1, 161.2,142.6, 142.1, 135.4, 131.5, 129.5, 124.3, 124.0, 123.5, 120.7, 109.5,109.0, 80.5, 57.7, 44.5, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z386.5 (M+1).

Example 40 Synthesis of1′-pentyl-6-(phenylsulfonyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 39, and makingnon-critical variations using sodium phenyl sulfinate to replace sodiummethanesulfinate, the title compound was obtained (50%) as a yellowishoil: ¹H NMR (300 MHz, CDCl_(3,)) δ 7.94-7.88 (m, 2H), 7.60-7.44 (m, 4H),7.40 (dd, 1H), 7.31 (dt, 1H), 7.10-6.99 (m, 2H), 6.92 (d, 1H), 6.78 (d,1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.84-3.61 (m, 2H), 1.75-1.65 (m, 2H),1.39-1.30 (m, 4H), 0.88 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.1, 161.2,143.2, 142.5, 141.2, 134.9, 133.3, 129.4, 129.3, 127.8, 124.1, 124.0,123.5, 121.1, 109.8, 108.9, 80.5, 57.7, 40.5, 29.0, 27.1, 22.3, 14.0; MS(ES+) m/z 448.5 (M+1).

Example 41 Synthesis of1′-pentyl-5-phenoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 36, and makingnon-critical variations using5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, the titlecompound was obtained (10% yield) as a colorless oil: ¹H NMR (300 MHz,CDCl₃) δ 7.32-7.10 (m, 5H), 7.06-6.82 (m, 6H), 6.42 (d, 1H), 4.95 (d,1H), 4.71 (d, 1H), 3.82-3.62 (m, 2H), 1.75-1.63 (m, 2H), 1.43-1.34 (m,4H), 0.85 (t, 3H); MS (ES+) m/z 400.4 (M+1).

Example 42 Synthesis of1′-(diphenylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A mixture of of5-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(3.00 g, 6.22 mmol), bis(pinacolato)diboron (1.80 g, 7.09 mmol),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.45 g, 9mole %), and potassium acetate (5.49 g, 56.0 mmol) in anhydrous dimethylsulfoxide (40.0 mL) was stirred at 100° C. under N₂ for 16 h. Thereaction mixture was diluted with water (600 mL). The aqueous mixturewas extracted with ethyl acetate (3×200 mL). The combined organic layerswas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/6) to give the title compound(1.00 g, 30%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.68 (dd, 1H),7.40-7.25 (m, 10H), 7.18 (br, 1H), 7.11 (dd, 1H), 7.06-6.91 (m, 4H),6.50 (d, 1H), 4.99 (d, 1H), 4.74 (d, 1H), 1.27 (d, 12H); MS (ES+) m/z530.32 (M+1).

Example 43 Synthesis of1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A mixture of1′-(diphenylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(4.50 g, 8.50 mmol), hydrogen peroxide (4.86 mL, 30% solution, 42.5mmol), sodium hydroxide (16.38 mL, 10% solution, 40.82 mmol) in methanolwas stirred at 0° C. for 30 min and ambient temperature for 16 h. Thereaction mixture was quenched with sodium bisulfite. The pH of thereaction mixture was adjusted to 4 using 14% hydrochloric acid. Themixture was extracted with ethyl acetate (3×250 mL). The combinedorganic layers was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo. The residue was triturated withhexane (20.0 mL), followed by ether (15.0 mL) to give the title compound(3.20 g, 90%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.38 (m,10H), 7.13 (dd, 1H), 7.07-6.91 (m, 3H), 6.79 (d, 1H), 6.63 (dd, 1H),6.50 (d, 1H), 6.12 (d, 1H), 4.96 (d, 1H), 4.69 (d, 1H); MS (ES+) m/z420.23 (M+1).

Example 44 Synthesis of5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.28, and makingnon-critical variations using1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,the title compound was obtained (48%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 10.58 (s, 1H), 8.85 (s, 1H), 7.21 (dt, 1H), 7.06 (d, 1H),6.94 (dd, 1H), 6.89 (d, 1H), 6.72 (d, 1H), 6.54 (dd, 1H), 6.02 (d, 1H),4.70 (d, 1H), 4.57 (d, 1H); MS (ES+) m/z 254.2 (M+1).

Example 45 Synthesis of2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yltrifluoromethanesulfonate

To a mixture of 5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.18 g, 0.70 mmol) and trifluoromethane sulfonic anhydride (0.26 g,0.91 mmol) in dichloromethane (5.00 mL) was added triethylamine (0.14 g,1.93 mmol) at 0° C. The reaction mixture was stirred at ambienttemperature for 16 h and diluted with dichloromethane (100 mL). Afterwashing with aqueous saturated sodium chloride (2×20.0 mL), the organiclayer was dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexane, 1/2) to give the title compound(0.07 g, 25%) as a light yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.92(br, 1H), 7.29 (dt, 1H), 7.15-7.03 (m, 3H), 7.99-6.94 (m, 2H), 6.69 (d,1H), 5.03 (d, 1H), 4.76 (d, 1H); MS (ES+) m/z 386.5 (M+1).

Example 46 Synthesis of2′-oxo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yltrifluoromethanesulfonate

To a mixture of 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yltrifluoromethanesulfonate (0.42 g, 1.10 mmol) and sodium hydroxide (0.07g, 1.65 mmol) in N,N-dimethylformamide (5.00 mL) was added2-(bromomethyl)-5-(trifluoromethyl)furan (0.50 g, 2.20 mmol) at 0° C.The reaction mixture was stirred at ambient temperature for 16 h anddiluted with ethyl acetate (200 mL). After washing with aqueoussaturated sodium chloride (2×20.0 mL), the organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo. The residue was subjected to column chromatography (ethylacetate/hexane, 1/3) to give the title compound (0.47 g, 80%) as a clearoil: ¹H NMR (300 MHz, CDCl₃) δ 7.34 (t, 1H), 7.18-6.94 (m, 5H), 6.74(dd, 1H), 6.55 (dd, 1H), 6.40 (d, 1H), 5.09-4.72 (m, 4H); MS (ES+) m/z534.4 (M+1).

Example 47 Synthesis of5-pyridin-3-yl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 4.2, and makingnon-critical variations using2′-oxo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yltrifluoromethanesulfonate to replace2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide,and pyridin-3-ylboronic acid to replace pyrimidine-5-boronic acid,5-pyridin-3-yl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (74%) as a white solid, which was treated with HCl in etherto give the title compound: mp 98-100° C.; ¹H NMR (300 MHz, CD₃OD) δ8.96 (br, 1H), 8.74-8.65 (m, 2H), 8.04 (dd, 1H), 7.73 (dd, 1H), 7.37(dt, 1H), 7.25-7.09 (m, 5H), 6.95 (dd, 1H), 6.67 (d, 1H), 5.20-4.83 (m,4H); ¹³C NMR (75 MHz, CD₃OD) δ 175.7, 161.3, 151.1, 142.1, 140.2, 138.6,137.5, 137.4, 130.0, 129.4, 128.1, 127.5, 125.6, 125.5, 122.3, 122.1,120.8, 111.4, 111.3, 109.7, 108.1, 107.7, 78.7, 58.3, 34.9; MS (ES+) m/z463.1 (M+1).

Example 48 Synthesis of1′-pentyl-5-pyridin-3-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.2, and makingnon-critical variations using5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide,and pyridin-3-ylboronic acid to replace pyrimidine-5-boronic acid, thetitle compound was obtained (70%) was obtained as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 8.55 (br, 1H), 7.65 (d, 1H), 7.45-6.98 (m, 7H), 6.92(d, 1H), 6.85 (d, 1H), 4.98 (d, 1H), 4.72 (d, 1H), 3.89-3.64 (m, 2H),1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.86 (t, 3H); MS (ES+) m/z 385.5(M+1).

Example 49 Synthesis of1′-pentyl-5-pyrimidin-5-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.2, and makingnon-critical variations using5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide,the title compound was obtained (40%) was obtained as a white solid: mp115-117° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.08 (s, 1H), 8.74 (s, 1H), 7.41(dd, 1H), 7.33 (dt, 1H), 7.16 (dd, 1H), 7.11-7.01 (m, 2H), 6.95 (d, 1H),6.86 (d, 1H), 5.01 (d, 1H), 4.75 (d, 1H), 3.89-3.64 (m, 2H), 1.80-1.68(m, 2H), 1.43-1.34 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 386.4 (M+1).

Example 50 Synthesis of1′-pentyl-5-pyridin-4-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.2, and makingnon-critical variations using5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide,and pyridin-4-ylboronic acid to replace pyrimidine-5-boronic acid, thetitle compound was obtained (95%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 8.55-8.47 (m, 2H), 7.52-7.46 (dd, 1H), 7.35-7.26 (m, 3H), 7.15(dd, 1H), 7.07-7.00 (m, 2H), 6.97-6.92 (m, 2H), 4.99 (d, 1H), 4.73 (d,1H), 3.89-3.67 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t,3H); MS (ES+) m/z 385.5 (M+1).

Example 51 Synthesis of2′-oxo-1′-pentyl-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 30, and makingnon-critical variations using5-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′(1′H)-one,the title compound was obtained (78%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.51 (dt, 1H), 7.34 (dt, 1H), 7.12-6.91 (m, 5H), 5.01 (d, 1H),4.76 (d, 1H), 3.86-3.63 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.32 (m, 4H),0.92 (t, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.2, 164.1, 142.6, 134.8,131.4, 130.8, 129.6, 127.8, 123.9, 123.5, 118.8, 111.5, 109.1, 104.7,80.6, 57.3, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 333.5 (M+1).

Example 52 Synthesis ofN-(2-fluorophenyl)-2-(2′-oxo-5-pyridin-3-ylspiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 37, and makingnon-critical variations using2-(5-bromo-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamideto replace 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,the title compound was obtained (55% yield) was obtained as a whitesolid: mp 98-100° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.60-8.53 (m, 2H), 8.14(dd, 1H), 7.65 (dd, 1H), 7.41 (dd, 1H), 7.32-6.90 (m, 11H), 5.02 (d,1H), 4.76 (d, 1H), 4.72 (d, 1H), 4.56 (d, 1H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 164.8, 160.9, 154.2, 151.0, 147.1, 141.7, 134.2, 131.7, 131.5,129.9, 129.4, 129.1, 125.1, 124.6, 124.5, 124.2, 124.0, 122.5, 122.2,115.1, 114.8, 111.0, 109.1, 80.0, 58.1, 44.6; MS (ES+) m/z 466.4 (M+1).

Example 53 Synthesis of1′-[(5-fluoro-1H-benzimidazol-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)aceticacid (0.50 g, 1.47 mmol) and 4-fluorobenzene-1,2-diamine (0.15 g, 1.18mmol) in anhydrous toluene (20.0 mL) was refluxed overnight under N₂.The reaction mixture was diluted with water (250 mL) and extracted withethyl acetate (2×200 mL). The combined organic extracts was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatography(ethyl acetate/hexane, 2/1) to give the title compound (0.13 g, 22%): mp138-142° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.39 (m, 1H), 7.32-7.22 (m,2H), 7.16-6.93 (m, 3H), 6.18 (s, 1H), 6.07 (s, 1H), 5.84-5.78 (m, 2H),5.20-5.14 (m, 2H), 4.98 (d, 1H), 4.60 (d, 1H); ¹³C NMR (75 MHz, CDCl₃) δ179.2, 161.3, 158.1, 156.2, 149.2, 149.1, 142.5, 141.2, 131.5, 129.5,124.4, 124.0, 118.0, 111.6, 111.2, 109.9, 103.1, 101.7, 93.5, 80.5,58.5, 38.9; MS (ES+) m/z 430.2 (M+1).

Example 54 Synthesis of1′-(diphenylmethyl)-5-pyridin-3-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.2, and makingnon-critical variations using5-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one toreplace2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide,and pyridin-3-ylboronic acid to replace pyrimidine-5-boronic acid, thetitle compound was obtained (74%) as a white solid: mp 204-207° C.; ¹HNMR (300 MHz, CDCl₃) δ 8.62-8.46 (m, 2H), 7.62 (d, 1H), 7.43-7.26 (m,11H), 7.16 (dd, 1H), 7.03-6.94 (m, 4H), 6.76 ((d, 1H), 6.54 (d, 1H),5.09 (d, 1H), 4.82 (d, 1H); MS (ES+) m/z 481.5 (M+1).

Example 55 Synthesis of tert-butyl3-(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl)piperidine-1-carboxylate

A. Synthesis of5-piperidin-3-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.28, and makingnon-critical variations using1′-(diphenylmethyl)-5-pyridin-3-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,the title compound was obtained that was used in the next step.

B. Synthesis of tert-butyl3-(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl)piperidine-1-carboxylate

To a mixture of5-piperidin-3-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,triethylamine (0.95 g, 9.36 mmol) in anhydrous dichloromethane (15.0 mL)was added di-tert-butyl dicarbonate (1.02 g, 4.68 mmol) at 0° C. Thereaction mixture was stirred at ambient temperature and stirred overnight under N₂, diluted with dichloromethane (100 mL) and filteredthrough celite. The filtrate was concentrated in vacuo to dryness. Thebrown residue was subjected to column chromatography (ethylacetate/hexane, 1/1) to give the title compound (0.50 g, 40%) as a whitesolid: mp 120-123° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.82 (br, 1H),7.23-7.21 (m, 2H), 7.14-6.86 (m, 5H), 6.63 (br, 1H), 4.95 (d, 1H), 4.69(d, 1H), 4.10-4.00 (m, 2H), 2.70-2.45 (m, 2H), 1.95-1.80 (m, 2H),1.48-1.38 (m, 11H); MS (ES+) m/z 443.4 (M+1).

Example 56 Synthesis of tert-butyl3-(2′-oxo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl)piperidine-1-carboxylate

Following the procedure as described in PREPARATION 1A, and makingnon-critical variations using tert-butyl3-(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl)piperidine-1-carboxylateto replace 4-bromoindole, and 2-(bromomethyl)-5-(trifluoromethyl)furanto replace 1-bromopentane, the title compound was obtained (10%) as awhite solid: mp 59-61° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.23 (m, 2H),7.12 (d, 1H), 7.04-6.96 (m, 2H), 6.89 (d, 1H), 6.75 (s, 1H), 6.50 (s,1H), 6.41(s, 1H), 5.10-4.86 (m, 3H), 4.66 (d, 1H), 4.16-3.94 (m, 2H),2.68-2.38 (m, 2H), 1.90-1.60 (m, 3H), 1.40 (s, 10H), 1.27-1.21 (m, 1H);MS (ES+) m/z 591.2 (M+23).

Example 57 Synthesis of5-pyridin-4-yl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 4.2, and makingnon-critical variations using2′-oxo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yltrifluoromethanesulfonate to replace2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide,and pyridin-4-ylboronic acid to replace pyrimidine-5-boronic acid,5-pyridin-4-yl-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained as a white solid, which was treated with HCl in ether togive the title compound (54%): mp 108-110° C.; ¹H NMR (300 MHz, CDCl₃) δ8.57-8.47 (m, 2H), 7.52 (dd, 1H), 7.37-7.29 (m, 3H), 7.18 (dd, 1H),7.12-7.00 (m, 3H), 6.92 (d, 1H), 6.75 (dd, 1H), 6.43 (d, 1H), 5.11 4.83(m, 3H), 4.75 (d, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 176.2, 164.3, 156.7,151.5, 141.5, 140.8, 131.5, 131.1, 130.7, 129.8, 127.7, 124.3, 124.1,123.4, 123.1, 112.9, 112.2, 110.0, 109.4, 80.9, 57.5, 37.3; MS (ES+) m/z466.4 (M+1).

Example 58 Synthesis of5-methoxy-1′-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a mixture of 5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.10 g, 0.39 mmol), triphenylphosphine (0.20 g, 0.76 mmol) and methanol(0.05 g, 1.6 mmol) in anhydrous tetrahydrofuran was added diethylazodicarboxylate (0.14 g, 0.80 mmol) at 0° C. The reaction mixture wasstirred at ambient temperature under N₂ for 16 h and concentrated invacuo to dryness. The brown residue was subjected to columnchromatography (ethyl acetate/hexane, 1/1) to give the title compound(0.02 g, 14% yield) as a yellowish solid: mp 159-161° C.; ¹H NMR (300MHz, CDCl₃) δ 7.32 (dt, 1H), 7.14 (d, 1H), 7.05 (t, 1H), 6.93-6.83 (m,2H), 6.74 (dd, 1H), 6.25 (d, 1H), 4.89 (d, 1H), 4.63 (d, 1H), 3.63 (s,3H), 3.28 (s, 3H); MS (ES+) 282.3 (M+1).

Example 59 Synthesis ofN-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]-2-(trifluoromethoxy)benzamide

Following the procedure as described in EXAMPLE 17, and makingnon-critical variations using1′-(2-aminoethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace1′-(3-aminopropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and 2-(trifluoromethoxy)benzoyl chloride to replace3-chlorothiophene-2-carbonyl chloride, the title compound was obtained(91%) as a colorless solid: mp 183-184° C.; ¹H NMR (300 MHz, CDCl₃) δ7.86-7.83 (m, 1H), 7.50-7.45 (m, 1H), 7.37-7.27 (m, 3H), 7.16-7.11 (m,2H), 7.07-7.02 (m, 1H), 6.84 (t, 1H), 6.47 (s, 1H), 6.10 (s, 1H), 5.82(dd, 2H), 4.87 (d, 1H), 4.64 (d, 1H), 4.10-3.94 (m, 2H), 3.90-3.68 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 165.0, 155.9, 148.8, 145.9, 142.3,141.9, 132.4, 132.1, 131.3, 129.2, 127.6, 127.3, 124.0, 123.6, 121.2,121.1, 119.2, 108.7, 103.0, 101.4, 93.6, 80.4, 58.2, 39.5, 38.2; MS(ES+) m/z 513.4 (M+1).

Biological Assays

Various techniques are known in the art for testing the activity ofcompounds of the invention. In order that the invention described hereinmay be more fully understood, the following biological assays are setforth. It should be understood that these examples are for illustrativepurposes only and are not to be construed as limiting this invention inany manner.

Biological Example 1 Guanidine Influx Assay (In Vitro Assay)

This example describes an in vitro assay for testing and profiling testagents against human or rat sodium channels stably expressed in cells ofeither an endogenous or recombinant origin. The assay is also useful fordetermining the IC-50 of a sodium channel blocking compound. The assayis based on the guanidine flux assay described by Reddy, N. L., et al.,J Med Chem (1998), 41(17):3298-302.

The guanidine influx assay is a radiotracer flux assay used to determineion flux activity of sodium channels in a high-throughputmicroplate-based format. The assay uses ¹⁴C-guanidine hydrochloride incombination with various known sodium channel modulators, to assay thepotency of test agents. Potency is determined by an IC-50 calculation.Selectivity is determined by comparing potency of the compound for thechannel of interest to its potency against other sodium channels (alsocalled ‘selectivity profiling’).

Each of the test agents is assayed against cells that express thechannels of interest. Voltage gated sodium channels are either TTXsensitive or insensitive. This property is useful when evaluating theactivities of a channel of interest when it resides in a mixedpopulation with other sodium channels. The following Table 1 summarizescell lines useful in screening for a certain channel activity in thepresence or absence of TTX.

TABLE 1 CELL LINE mRNA Expression Functional Characterization CHO-K1(Chinese Na_(v)1.4 expression has been The 18-20-fold increase in [¹⁴C]Hamster Ovary; shown by RT-PCR Guanidine influx was completelyrecommended No other Na_(v) expression has blocked using TTX. (Na_(v)1.4is a host cell line) been detected TTX sensitive channel) ATTC accessionnumber CCL-61 L6 (rat myoblast Expression of Nav1.4 and 1.5 The 10-15fold increase in [¹⁴C] cell) ATTC Guanidine influx was only NumberCRL-1458 partially blocked by TTX (Na_(v)1.5 is TTX resistant SH-SY5Y(Human Published Expression of The 10-16-fold increase in [¹⁴C]neuroblastoma) Na_(v)1.9 and Na_(v)1.7 (Blum et Guanidine influx aboveATTC Number al) background. CRL-2266 was partially blocked by TTX(Na_(v)1.9 is TTX resistant SK-N-BE2C (a Expression of NaV1.8Stimulation of BE2C cells with human pyrethroids results in a 6 foldneuroblastoma cell increase in [¹⁴C] Guanidine influx line ATCC Numberabove background. CRL-2268) TTX partially blocked influx (NaV1.8 is TTXresistant) PC12 (rat Expression of Na_(v)1.2 The 8-12-fold increase in[¹⁴C] pheochromocytoma) expression Guanidine influx was completely ATTCNumber blocked using TTX. (Na_(v)1.2 is a CRL-1721 TTX sensitivechannel)

It is also possible to employ recombinant cells expressing these sodiumchannels. Cloning and propagation of recombinant cells are known tothose skilled in the art (see, for example, Klugbauer, N, et al., EMBOJ. (1995), 14(6):1084-90; and Lossin, C., et al., Neuron (2002), 34, pp.877-884)

Cells expressing the channel of interest are grown according to thesupplier or in the case of a recombinant cell in the presence ofselective growth media such as G418 (Gibco/Invitrogen). The cells aredisassociated from the culture dishes with an enzymatic solution (1×)Trypsin/EDTA (Gibco/Invitrogen) and analyzed for density and viabilityusing haemocytometer (Neubauer). Disassociated cells are washed andresuspended in their culture media then plated into Scintiplates(Beckman Coulter Inc.) (approximately 100,000 cells/well) and incubatedat 37° C./5% CO_(2.) for 20-24 hours. After an extensive wash with Lowsodium HEPES-buffered saline solution (LNHBSS) (150 mM Choline Chloride,20 nM HEPES (Sigma), 1 mM Calcium Chloride, 5 mM Potassium Chloride, 1mM Magnesium Chloride, 10 mM Glucose) agents diluted with LNHBSS areadded to each well. (Varying concentrations of test agent may be used).The activation/radiolabel mixture contains aconitine (Sigma), and¹⁴C-guanidine hydrochloride (ARC).

After loading the cells with test agent and activation/radiolabelmixture, the Scintiplates are incubated at ambient temperature.Following the incubation, the Scintplates are extensively washed withLNHBSS supplemented with guanidine (Sigma). The Scintiplates are driedand then counted using a Wallac MicroBeta TriLux (Perkin-Elmer LifeSciences). The ability of the test agent to block sodium channelactivity is determined by comparing the amount of ¹⁴C-guanidine presentinside the cells expressing the different sodium channels. Based on thisdata, a variety of calculations, as set out elsewhere in thisspecification, may be used to determine whether a test agent isselective for a particular sodium channel.

IC-50 value of a test agent for a specific sodium channel may bedetermined using the above general method. IC-50 may be determined usinga 3, 8, 10, 12 or 16 point curve in duplicate or triplicate with astarting concentration of 1, 5 or 10 μM diluted serially with a finalconcentration reaching the sub-nanomolar, nanomolar and low micromolarranges. Typically the mid-point concentration of test agent is set at 1μM, and sequential concentrations of half dilutions greater or smallerare applied (e.g. 0.5 μM; 5 μM and 0.25 μM; 10 μM and 0.125 μM; 20 μMetc.). The IC-50 curve is calculated using the 4 Parameter LogisticModel or Sigmoidal Dose-Response Model formula(fit=(A+((B−A)/(1+((C/x)̂D)))).

The fold selectivity, factor of selectivity or multiple of selectivity,is calculated by dividing the IC-50 value of the test sodium channel bythe reference sodium channel, for example, Na_(v)1.5.

Biological Example 2 Electrophysiological Assay (In Vitro Assay)

Cells expressing the channel of interest were cultured in DMEM growthmedia (Gibco) with 0.5 mg/mL G418, ±1% PSG, and 10% heat-inactivatedfetal bovine serum at 37° C. and 5% CO₂. For electrophysiologicalrecordings, cells were plated on 10 mm dishes.

Whole cell recordings were examined by established methods of whole cellvoltage clamp (Bean et al., op. cit.) using an Axopatch 200B amplifierand Clampex software (Axon Instruments, Union City, Calif.). Allexperiments were performed at ambient temperature. Electrodes werefire-polished to resistances of 2-4 Mohms Voltage errors and capacitanceartifacts were minimized by series resistance compensation andcapacitance compensation, respectively. Data were acquired at 40 kHz andfiltered at 5 kHz. The external (bath) solution consisted of: NaCl (140mM), KCl (5 mM), CaCl₂ (2 mM), MgCl₂ (1 mM), HEPES (10 mM) at pH 7.4.The internal (pipette) solution consisted of (in mM): NaCl (5), CaCl₂(0.1) MgCl₂ (2), CsCl (10), CsF (120), HEPES (10), EGTA (10), at pH 7.2.

To estimate the steady-state affinity of compounds for the resting andinactivated state of the channel (K_(r) and K_(i), respectively), 12.5ms test pulses to depolarizing voltages from −60 to +90 mV from aholding potential of −110 mV was used to construct current-voltagerelationships (I-V curves). A voltage near the peak of the IV-curve (−30to 0 mV) was used as the test pulse throughout the remainder of theexperiment. Steady-state inactivation (availability) curves were thenconstructed by measuring the current activated during a 8.75 ms testpulse following 1 second conditioning pulses to potentials ranging from−110 to −10 mV. To monitor channels at steady-state, a single “diary”protocol with a holding potential of −110 mV was created to record theresting state current (10 ms test pulse), the current after fastinactivation (5 ms pre-pulse of −80 to −50 mV followed by a 10 ms testpulse), and the current during various holding potentials (35 ms ramp totest pulse levels). Compounds were applied during the “diary” protocoland the block was monitored at 15 s intervals.

After the compounds equilibrated, the voltage-dependence of thesteady-state inactivation in the presence of the compound wasdetermined. Compounds that block the resting state of the channeldecreased the current elicited during test pulses from all holdingpotentials, whereas compounds that primarily blocked the inactivatedstate decreased the current elicited during test pulses at moredepolarized potentials. The currents at the resting state (I_(rest)) andthe currents during the inactivated state (I_(inactivated)) were used tocalculate steady-state affinity of compounds. Based on theMichaelis-Menton model of inhibition, the K_(r) and K_(i) was calculatedas the concentration of compound needed to cause 50% inhibition of theI_(rest) or the I_(inactivated), respectively.

${\% \mspace{14mu} {inhibition}} = \frac{{V_{\max}^{*}\lbrack{Drug}\rbrack}^{h}}{\lbrack{Drug}\rbrack^{h} + K_{m}^{h}}$

V_(max) is the rate of inhibition, h is the Hill coefficient (forinteracting sites), K_(m) is Michaelis-Menten constant, and [Drug] isthe concentration of the test compound. At 50% inhibition (½V_(max)) ofthe I_(rest) or I_(inactivated), the drug concentration is numericallyequal to K_(m) and approximates the K_(r) and K_(i), respectively.

Biological Example 3 Analgesia Induced by Sodium Channel Blockers HeatInduced Tail Flick Latency Test

In this test, the analgesia effect produced by administering a compoundof the invention was observed through heat-induced tail-flick in mice.The test includes a heat source consisting of a projector lamp with alight beam focused and directed to a point on the tail of a mouse beingtested. The tail-flick latencies, which were assessed prior to drugtreatment, and in response to a noxious heat stimulus, i.e., theresponse time from applying radiant heat on the dorsal surface of thetail to the occurrence of tail flick, were measured and recorded at 40,80, 120, and 160 minutes.

For the first part of this study, 65 animals underwent assessment ofbaseline tail flick latency once a day over two consecutive days. Theseanimals were then randomly assigned to one of the 11 different treatmentgroups including a vehicle control, a morphine control, and 9 compoundsat 30 mg/kg were administered intramuscularly. Following doseadministration, the animals were closely monitored for signs of toxicityincluding tremor or seizure, hyperactivity, shallow, rapid or depressedbreathing and failure to groom. The optimal incubation time for eachcompound was determined via regression analysis. The analgesic activityof the test compounds was expressed as a percentage of the maximumpossible effect (% MPE) and was calculated using the following formula:

$\% \mspace{14mu} {MPE}\frac{{{Postdrug}\mspace{14mu} {latency}} - {{Predrug}\mspace{14mu} {latency}}}{{{Cut}\text{-}{off}\mspace{14mu} {time}\mspace{14mu} \left( {10\mspace{11mu} s} \right)} - {{Predrug}\mspace{14mu} {latency}}} \times 100\%$

where:

Postdrug latency=the latency time for each individual animal takenbefore the tail is removed (flicked) from the heat source afterreceiving drug.

Predrug latency=the latency time for each individual animal taken beforethe tail is flicked from the heat source prior to receiving drug.

Cut-off time (10 s)=is the maximum exposure to the heat source.

Acute Pain (Formalin Test)

The formalin test is used as an animal model of acute pain. In theformalin test, animals were briefly habituated to the plexiglass testchamber on the day prior to experimental day for 20 minutes. On the testday, animals were randomly injected with the test articles. At 30minutes after drug administration, 50 μL of 10% formalin was injectedsubcutaneously into the plantar surface of the left hind paw of therats. Video data acquisition began immediately after formalinadministration, for duration of 90 minutes.

The images were captured using the Actimetrix Limelight software whichstores files under the *.llii extension, and then converts it into theMPEG-4 coding. The videos are then analyzed using behaviour analysissoftware “The Observer 5.1”, (Version 5.0, Noldus InformationTechnology, Wageningen, The Netherlands). The video analysis was done bywatching the animal behaviour and scoring each according to type, anddefining the length of the behaviour (Dubuisson and Dennis, 1977).Scored behaviours include: (1) normal behaviour, (2) putting no weighton the paw, (3) raising the paw, (4) licking/biting or scratching thepaw. Elevation, favoring, or excessive licking, biting and scratching ofthe injected paw indicate a pain response. Analgesic response orprotection from compounds is indicated if both paws are resting on thefloor with no obvious favoring, excessive licking, biting or scratchingof the injected paw.

Analysis of the formalin test data is done according to two factors: (1)Percent Maximal Potential Inhibitory Effect (% MPIE) and (2) pain score.The % MPIEs was calculated by a series of steps, where the first is tosum the length of non-normal behaviours (behaviours 1, 2, 3) of eachanimal. A single value for the vehicle group was obtained by averagingall scores within the vehicle treatment group. The following calculationyields the MPIE value for each animal:

MPIE (%)=100−[(treatment sum/average vehicle value)×100%]

The pain score is calculated from a weighted scale as described above.The duration of the behaviour is multiplied by the weight (rating of theseverity of the response), and divided by the total length ofobservation to determine a pain rating for each animal. The calculationis represented by the following formula:

Pain rating=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)

Compounds of the present invention were shown to be efficacious within arange of 30 mg/kg and 0.1 mg/kg.

CFA Induced Chronic Inflammatory Pain

In this test, tactile allodynia was assessed with calibrated von Freyfilaments. Following a full week of acclimatization to the vivariumfacility, 150 μL of the “Complete Freund's Adjuvant” (CFA) emulsion (CFAsuspended in an oil/saline (1:1) emulsion at a concentration of 0.5mg/mL) was injected subcutaneously into the plantar surface of the lefthind paw of rats under light isoflurane anaesthesia. Animals wereallowed to recover from the anaesthesia and the baseline thermal andmechanical nociceptive thresholds of all animals are assessed one weekafter the administration of CFA. All animals were habituated to theexperimental equipment for 20 minutes on the day prior to the start ofthe experiment. The test and control articles were administrated to theanimals, and the nociceptive thresholds measured at defined time pointsafter drug administration to determine the analgesic responses to eachof the six available treatments. The time points used were previouslydetermined to show the highest analgesic effect for each test compound.

Thermal nociceptive thresholds of the animals were assessed using theHargreaves test. Animals were placed in a Plexiglas enclosure set on topof an elevated glass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 30° C. forall test trials. Animals were allowed to accommodate for 20 minutesfollowing placement into the enclosure until all exploration behaviourceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter (IITC,Woodland Hills, Calif.) was used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source were set at 1 and 45 respectively, and a cut off time of 20seconds was employed to prevent tissue damage.

The response thresholds of animals to tactile stimuli were measuredusing the Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.) following the Hargreaves test. Animals wereplaced in an elevated Plexiglas enclosure set on a mire mesh surface.After 10 minutes of accommodation, pre-calibrated Von Frey hairs wereapplied perpendicularly to the plantar surface of both paws of theanimals in an ascending order starting from the 0.1 g hair, withsufficient force to cause slight buckling of the hair against the paw.Testing continues until the hair with the lowest force to induce a rapidflicking of the paw is determined or when the cut off force ofapproximately 20 g is reached. This cut off force was used because itrepresent approximately 10% of the animals' body weight and it serves toprevent raising of the entire limb due to the use of stiffer hairs,which would change the nature of the stimulus. The compounds of thepresent invention were shown to be efficacious within a range of 30mg/Kg and 0.1 mg/Kg.

Postoperative Models of Nociception

In this model, the hypealgesia caused by an intra-planar incision in thepaw is measured by applying increased tactile stimuli to the paw untilthe animal withdraws its paw from the applied stimuli. While animalswere anaesthetized under 3.5% isofluorane, which was delivered via anose cone, a 1 cm longitudinal incision was made using a number 10scalpel blade in the plantar aspect of the left hind paw through theskin and fascia, starting 0.5 cm from the proximal edge of the heel andextending towards the toes. Following the incision, the skin was apposedusing 2, 3-0 sterilized silk sutures. The injured site was covered withPolysporin and Betadine. Animals were returned to their home cage forovernight recovery.

The withdrawal thresholds of animals to tactile stimuli for bothoperated (ipsilateral) and unoperated (contralateral) paws can bemeasured using the Model 2290 Electrovonfrey anesthesiometer (IITC LifeScience, Woodland Hills, Calif.). Animals were placed in an elevatedPlexiglas enclosure set on a mire mesh surface. After at least 10minutes of acclimatization, pre-calibrated Von Frey hairs were appliedperpendicularly to the plantar surface of both paws of the animals in anascending order starting from the 10 g hair, with sufficient force tocause slight buckling of the hair against the paw. Testing continueduntil the hair with the lowest force to induce a rapid flicking of thepaw is determined or when the cut off force of approximately 20 g isreached. This cut off force is used because it represent approximately10% of the animals' body weight and it serves to prevent raising of theentire limb due to the use of stiffer hairs, which would change thenature of the stimulus.

Compounds of the present invention were shown to be efficacious within arange of 30 mg/Kg and 0.1 mg/Kg.

Neuropathic Pain Model; Chronic Constriction Injury

Briefly, an approximately 3 cm incision was made through the skin andthe fascia at the mid thigh level of the animals' left hind leg using ano. 10 scalpel blade. The left sciatic nerve was exposed via bluntdissection through the biceps femoris with care to minimizehaemorrhagia. Four loose ligatures were tied along the sciatic nerveusing 4-0 non-degradable sterilized silk sutures at intervals of 1 to 2mm apart. The tension of the loose ligatures was tight enough to induceslight constriction of the sciatic nerve when viewed under a dissectionmicroscope at a magnification of 4 fold. In the sham-operated animal,the left sciatic nerve was exposed without further manipulation.Antibacterial ointment was applied directly into the wound, and themuscle was closed using sterilized sutures. Betadine was applied ontothe muscle and its surroundings, followed by skin closure with surgicalclips.

The response thresholds of animals to tactile stimuli were measuredusing the Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals were placed in an elevated Plexiglasenclosure set on a mire mesh surface. After 10 minutes of accommodation,pre-calibrated Von Frey hairs were applied perpendicularly to theplantar surface of both paws of the animals in an ascending orderstarting from the 0.1 g hair, with sufficient force to cause slightbuckling of the hair against the paw. Testing continues until the hairwith the lowest force to induce a rapid flicking of the paw isdetermined or when the cut off force of approximately 20 g is reached.This cut off force is used because it represents approximately 10% ofthe animals' body weight and it serves to prevent raising of the entirelimb due to the use of stiffer hairs, which would change the nature ofthe stimulus. Compounds of the present invention were shown to beefficacious within a range of 30 mg/kg and 0.1 mg/Kg.

Thermal nociceptive thresholds of the animals were assessed using theHargreaves test. Following the measurement of tactile thresholds,animals were placed in a Plexiglass enclosure set on top of an elevatedglass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 24 to 26°C. for all test trials. Animals were allowed to accommodate for 10minutes following placement into the enclosure until all explorationbehaviour ceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter(IITC, Woodland Hills, Calif.) was used to apply a radiant heat beamfrom underneath the glass platform to the plantar surface of the hindpaws. During all test trials, the idle intensity and active intensity ofthe heat source were set at 1 and 55 respectively, and a cut off time of20 seconds was used to prevent tissue damage.

Biological Example 4 Aconitine Induced Arrhythmia Test

The antiarrhythmic activity of compounds of the invention isdemonstrated by the following test. Arrhythmia was provoked byintravenous administration of aconitine (2.0 μg/Kg) dissolved inphysiological saline solution. Test compounds of the invention wereintravenously administered 5 minutes after the administration ofaconitine. Evaluation of the anti-arrhythmic activity was conducted bymeasuring the time from the aconitine administration to the occurrenceof extrasystole (ES) and the time from the aconitine administration tothe occurrence of ventricular tachycardia (VT).

In rates under isoflurane anaesthesia (¼ to ⅓ of 2%), a tracheotomy wasperformed by first creating an incision in the neck area, then isolatingthe trachea and making a 2 mm incision to insert tracheal tube 2 cm intothe trachea such that the opening of the tube was positioned just on topof the mouth. The tubing was secured with sutures and attached to aventilator for the duration of the experiment.

Incisions (2.5 cm) were then made into the femoral areas and using ablunt dissection probe, the femoral vessels were isolated. Both femoralveins were cannulated, one for pentobarbital anaesthetic maintenance(0.02-0.05 mL) and one for the infusion and injection of drug andvehicle. The femoral artery was cannulated with the blood pressure gelcatheter of the transmitter.

The ECG leads were attached to the thoracic muscle in the Lead IIposition (upper right/above heart—white lead and lower left/belowheart—red lead). The leads were secured with sutures.

All surgical areas were covered with gauze moistened with 0.9% saline.Saline (1-1.5 mL of a 0.9% solution) was supplied to moisten the areaspost-surgery. The animals' ECG and ventillation were allowed toequilibrate for at least 30 minutes.

The arrhythmia was induced with a 2 μg/Kg/min aconitine infusion for 5minutes. During this time the ECG was recorded and continuouslymonitored. An intravenous bolus injection of a test compound of theinvention (10, 30 or 100 μg/kg) resulted in a complete return to normalbaseline ECG.

Accordingly, compounds of the invention, when tested in this model,demonstrated anti-arrhythmia activity.

Biological Example 5 Ischemia Induced Arrhythmia Test

Rodent models of ventricular arrhythmias, in both acute cardioversionand prevention paradigms have been employed in testing potentialtherapeutics for both atrial and ventricular arrhythmias in humans.Cardiac ischemia leading to myocardial infarction is a common cause ofmorbidity and mortality. The ability of a compound to preventischemia-induced ventricular tachycardia and fibrillation is an acceptedmodel for determining the efficacy of a compound in a clinical settingfor both atrial and ventricular tachycardia and fibrillation.

Anaesthesia is first induced by pentobarbital (i.p.), and maintained byan i.v. bolus infusion. Male SD rats have their trachea cannulated forartificial ventilation with room air at a stroke volume of 10 ml/Kg, 60strokes/minute. The right femoral artery and vein are cannulated withPE50 tubing for mean arterial blood pressure (MAP) recording andintravenous administration of compounds, respectively.

The chest was opened between the 4^(th) and 5^(th) ribs to create a 1.5cm opening such that the heart was visible. Each rat was placed on anotched platform and metal restraints were hooked onto the rib cageopening the chest cavity. A suture needle was used to penetrate theventricle just under the lifted atrium and exited the ventricle in adownward diagonal direction so that a >30% to <50% occlusion zone (OZ)would be obtained. The exit position was ˜0.5 cm below where the aortaconnects to the left ventricle. The suture was tightened such that aloose loop (occluder) was formed around a branch of the artery. Thechest was then closed with the end of the occluder accessible outside ofthe chest.

Electrodes were placed in the Lead II position (right atrium to apex)for ECG measurement as follows: one electrode inserted into the rightforepaw and the other electrode inserted into the left hind paw.

The body temperature, MAP, ECG, and heart rate were constantly recordedthroughout the experiment. Once the critical parameters had stabilized,a 1-2 minute recording was taken to establish the baseline values.Infusion of a compound of the invention or control substance wasinitiated once baseline values were established. After a 5-minuteinfusion of compound or control, the suture was pulled tight to ligatethe LCA and create ischemia in the left ventricle. The criticalparameters were recorded continuously for 20 minutes after ligation,unless the MAP reached the critical level of 20-30 mmHg for at least 3minutes, in which case the recording was stopped because the animalwould be declared deceased and was then sacrificed. The ability ofcompounds of the invention to prevent arrhythmias and sustainnear-normal MAP and HR was scored and compared to control.

Compound of the invention, when tested in this model, demonstatrated theability to prevent ischemia-induced ventricular tachycardia andfibrillation.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A compound of formula (I):

wherein: j and k are each independently 0, 1, 2 or 3; Q is —C(R^(1a))H—,—C(O)— or —CF₂—; R^(1a) is hydrogen or —OR⁵; R¹ is hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl,heteroaryl, heterocyclyl, —R⁸—C(O)R⁵, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵,—S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is 0, 1 or 2), —R⁸—OR⁵, —R⁸—CN,—R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵; or R¹ is aralkyl substituted by—C(O)N(R⁶)R⁷ where: R⁶ is hydrogen, alkyl, aryl or aralkyl; and R⁷ ishydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵, —R⁹—N(R⁴)R⁵, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heteroarylalkyl; or R⁶ and R⁷, together with the nitrogen to whichthey are attached, form a heterocyclyl or heteroaryl; and wherein eacharyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl group for R⁶ and R⁷may be optionally substituted by one or more substituents selected fromthe group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo,haloalkyl, —R⁸—CN, —R⁸—OR⁵, heterocyclyl and heteroaryl; or R¹ isaralkyl optionally substituted by one or more substituents selected fromthe group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo, haloalkyl, alkyl,nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl; or R¹ is—R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹ where: eachR¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl; each R¹¹ ishydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,—R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵, —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵,—R⁹—OR⁵, or —R⁹—CN; and R¹² is hydrogen, alkyl, aryl, aralkyl or—C(O)R⁵; and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groupfor R¹⁰ and R¹¹ may be optionally substituted by one or moresubstituents selected from the group consisting of alkyl, cycloalkyl,aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN, —R⁸—OR⁵, —R⁸—C(O)R⁵,heterocyclyl and heteroaryl; or R¹ is heterocyclylalkyl orheteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl groupis optionally substituted by one or more substituents selected from thegroup consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,—R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or 2),—R⁸—CN, or —R⁸—NO₂; R^(2a), R^(2b), R^(2c) and R^(2d) are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,—R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃, —R⁸—C(O)R⁴,—C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴, —R⁸—C(O)N(R⁴)R⁵,—C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴,—N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵, —N(R⁵)S(O)_(n)R⁴,—N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵, —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and—N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is independently 0, 1, or 2 andeach n is independently 1 or 2; and wherein each of the cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R^(2a),R^(2b), R^(2c) and R^(2d) may be optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,—R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵, —R⁸—C(O)R⁴,—R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and —N(R⁵)S(O)_(n)R⁴,wherein each m is independently 0, 1, or 2 and each n is independently 1or 2; or R^(2a) and R^(2b), together with the carbon ring atoms to whichthey are directly attached, may form a fused ring selected fromcycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d) areas defined above; or R^(2b) and R^(2c), together with the carbon ringatoms to which they are directly attached, may form a fused ringselected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a)and R^(2d) are as defined above; or R^(2c) and R^(2d), together with thecarbon ring atoms to which they are directly attached, may form a fusedring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, andR^(2a) and R^(2b) are as defined above; R^(3a), R^(3b), R^(3c) andR^(3d) are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN,—R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,—R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,—R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,—N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,—N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, 13 R⁸—S(O)_(n)N(R⁴)R⁵,—N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m isindependently 0, 1, or 2 and each n is independently 1 or 2; or R^(3a)and R^(3b), together with the carbon ring atoms to which they aredirectly attached, form a fused ring selected from cycloalkyl,heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d) are as definedabove; or R^(3b) and R^(3c), together with the carbon ring atoms towhich they are directly attached, may form a fused ring selected fromcycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d) areas defined above; or R^(3c) and R^(3d), together with the carbon ringatoms to which they are directly attached, may form a fused ringselected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a)and R^(3b) are as defined above; each R⁴ and R⁵ is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; orwhen R⁴ and R⁵ are each attached to the same nitrogen atom, then R⁴ andR⁵, together with the nitrogen atom to which they are attached, may forma heterocyclyl or heteroaryl; each R⁸ is a direct bond or a straight orbranched alkylene chain, a straight or branched alkenylene chain or astraight or branched alkynylene chain; and each R⁹ is a straight orbranched alkylene chain, a straight or branched alkenylene chain or astraight or branched alkynylene chain; as a stereoisomer, enantiomer,tautomer thereof or mixtures thereof; or a pharmaceutically acceptablesalt, solvate or prodrug thereof.
 2. The compound of claim 1 wherein: jis 0 and k is 1 or 2; Q is —C(R^(1a))H—, —C(O)— or —CF₂—; R^(1a) ishydrogen or —OR⁵; R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,—R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is 0,1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵; or R¹ isaralkyl substituted by —C(O)N(R⁶)R⁷ where: R⁶ is hydrogen, alkyl, arylor aralkyl; and R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵,—R⁹—N(R⁴)R⁵, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; or R⁶ and R⁷, togetherwith the nitrogen to which they are attached, form a heterocyclyl orheteroaryl; and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groupfor R⁶ and R⁷ may be optionally substituted by one or more substituentsselected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl,halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵, heterocyclyl and heteroaryl; or R¹ isaralkyl optionally substituted by one or more substituents selected fromthe group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo, haloalkyl, alkyl,nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl; or R¹ is—R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹ where: eachR¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl; each R¹¹ ishydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,—R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵, —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵,—R⁹—OR⁵, or —R⁹—CN; and R¹² is hydrogen, alkyl, aryl, aralkyl or—C(O)R⁵; and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groupfor R¹⁰ and R¹¹ may be optionally substituted by one or moresubstituents selected from the group consisting of alkyl, cycloalkyl,aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN, —R⁸—OR⁵, —R⁸—C(O)R⁵,heterocyclyl and heteroaryl; or R¹ is heterocyclylalkyl orheteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl groupis optionally substituted by one or more substituents selected from thegroup consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,—R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or 2),—R⁸—CN, or —R⁸—NO₂; R^(2a), R^(2b), R^(2c) and R^(2d) are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,—R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃, —R⁸—C(O)R⁴,—C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴, —R⁸—C(O)N(R⁴)R⁵,—C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴,—N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵, —N(R⁵)S(O)_(n)R⁴,—N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵, —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and—N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is independently 0, 1, or 2 andeach n is independently 1 or 2; and wherein each of the cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R^(2a),R^(2b), R^(2c) and R^(2d) may be optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,—R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵, —R⁸—C(O)R⁴,—R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and —N(R⁵)S(O)_(n)R⁴,wherein each m is independently 0, 1, or 2 and each n is independently 1or 2; or R^(2a) and R^(2b), together with the carbon ring atoms to whichthey are directly attached, may form a fused ring selected fromcycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d) areas defined above; or R^(2b) and R^(2c), together with the carbon ringatoms to which they are directly attached, may form a fused ringselected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a)and R^(2d) are as defined above; or R^(2c) and R^(2d), together with thecarbon ring atoms to which they are directly attached, may form a fusedring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, andR^(2a) and R^(2b) are as defined above; R^(3a), R^(3b), R^(3c) andR^(3d) are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN,—R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,—R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,—R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,—N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,—N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,—N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m isindependently 0, 1, or 2 and each n is independently 1 or 2; or R^(3a)and R^(3b), together with the carbon ring atoms to which they aredirectly attached, form a fused ring selected from cycloalkyl,heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d) are as definedabove; or R^(3b) and R^(3c), together with the carbon ring atoms towhich they are directly attached, may form a fused ring selected fromcycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d) areas defined above; or R^(3c) and R^(3d), together with the carbon ringatoms to which they are directly attached, may form a fused ringselected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a)and R^(3b) are as defined above; each R⁴ and R⁵ is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; orwhen R⁴ and R⁵ are each attached to the same nitrogen atom, then R⁴ andR⁵, together with the nitrogen atom to which they are attached, may forma heterocyclyl or heteroaryl; each R⁸ is a direct bond or a straight orbranched alkylene chain, a straight or branched alkenylene chain or astraight or branched alkynylene chain; and each R⁹ is a straight orbranched alkylene chain, a straight or branched alkenylene chain or astraight or branched alkynylene chain.
 3. The compound of claim 2wherein: j is 0 and k is 1 or 2; Q is —C(R^(1a))H—; R^(1a) is hydrogenor —OR⁵; R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,—R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is 0,1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵; R^(2a),R^(2b), R^(2c) and R^(2d) are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo,haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —R⁸—CN, —R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵,—S(O)_(m)R⁴, —OS(O)₂CF₃, —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵,—R⁸—C(O)OR⁴, —C(S)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴,—N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵,—N(R⁵)C(S)N(R⁴)R⁵, —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵,—R⁸—S(O)_(n)N(R⁴)R⁵, —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(═N—CN)N(R⁴)R⁵,wherein each m is independently 0, 1, or 2 and each n is independently 1or 2; and wherein each of the cycloalkyl, cycloalkylalkyl, aryl,aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl andheteroarylalkyl groups for R^(2a), R^(2b), R^(2c) and R^(2d) may beoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl,haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,—R⁸—CN, —R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵,—R⁸—C(O)R⁴, —R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and—N(R⁵)S(O)_(n)R⁴, wherein each m is independently 0, 1, or 2 and each nis independently 1 or 2; or R^(2a) and R^(2b), together with the carbonring atoms to which they are directly attached, may form a fused ringselected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c)and R^(2d) are as defined above; or R^(2b) and R^(2c), together with thecarbon ring atoms to which they are directly attached, may form a fusedring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, andR^(2a) and R^(2d) are as defined above; or R^(2c) and R^(2d), togetherwith the carbon ring atoms to which they are directly attached, may forma fused ring selected from cycloalkyl, aryl, heterocyclyl andheteroaryl, and R^(2a) and R^(2b) are as defined above; R^(3a), R^(3b),R^(3c) and R^(3d) are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo,haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —R⁸—CN—R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵,—S(O)_(m)R⁴, —OS(O)₂CF₃, —R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵,—R⁸—C(O)OR⁴, —C(S)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴,—N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵,—N(R⁵)C(S)N(R⁴)R⁵, —N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵,—R⁸—S(O)_(n)N(R⁴)R⁵, —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and—N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m is independently 0, 1, or 2and each n is independently 1 or 2; or R^(3a) and R^(3b), together withthe carbon ring atoms to which they are directly attached, form a fusedring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, andR^(3c) and R^(3d) are as defined above; or R^(3b) and R^(3c), togetherwith the carbon ring atoms to which they are directly attached, may forma fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl,and R^(3a) and R^(3d) are as defined above; or R^(3c) and R^(3d),together with the carbon ring atoms to which they are directly attached,may form a fused ring selected from cycloalkyl, heterocyclyl, aryl orheteroaryl, and R^(3a) and R^(3b) are as defined above; each R⁴ and R⁵is independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, andheteroarylalkyl; or when R⁴ and R⁵ are each attached to the samenitrogen atom, then R⁴ and R⁵, together with the nitrogen atom to whichthey are attached, may form a heterocyclyl or heteroaryl; each R⁹ is adirect bond or a straight or branched alkylene chain, a straight orbranched alkenylene chain or a straight or branched alkynylene chain;and each R⁹ is a straight or branched alkylene chain, a straight orbranched alkenylene chain or a straight or branched alkynylene chain. 4.The compound of claim 3 wherein: j is 0 and k is 1 or 2; Q is—C(R^(1a))H—; R^(1a) is hydrogen or —OR⁵; R¹ is hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl,heteroaryl, heterocyclyl, —R⁸—C(O)R⁵, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵,—S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is 0, 1 or 2), —R⁸—OR⁵, —R⁸—CN,—R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵; R^(2a), R^(2b), R^(2c) and R^(2d) areeach hydrogen; R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;R^(3a) and R^(3d) are each hydrogen; R^(3b) and R^(3c), together withthe carbon ring atoms to which they are directly attached, form a fusedring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; each R⁵is independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl and heteroaryl; each R⁸ is a direct bond ora straight or branched alkylene chain, a straight or branched alkenylenechain or a straight or branched alkynylene chain; and each R⁹ is astraight or branched alkylene chain, a straight or branched alkenylenechain or a straight or branched alkynylene chain.
 5. The compound ofclaim 4 wherein: j is 0 and k is 1 or 2; Q is —C(R^(1a))H—; R^(1a) ishydrogen or —OR⁵; R¹ is pentyl; R^(2a), R^(2b), R^(2c) and R^(2d) areeach hydrogen; R^(3a) and R^(3d) are each hydrogen; R^(3b) and R^(3c),together with the carbon ring atoms to which they are directly attached,form a fused dioxolyl ring; and R⁵ is selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl and heteroaryl.6. The compound of claim 5 selected from:1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one;1-pentyl-7′,8′-dihydro-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxol]-2(1H)-one;or7-methoxy-1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one.7. The compound of claim 2 wherein: j is 0 and k is 1 or 2; Q is —C(O)—or —CF₂—; R¹ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R⁸—C(O)R⁵,—R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵, —S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is 0,1 or 2), —R⁸—OR⁵, —R⁸—CN, —R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵; or R¹ isaralkyl substituted by —C(O)N(R⁶)R⁷ where: R⁶ is hydrogen, alkyl, arylor aralkyl; and R⁷ is hydrogen, alkyl, haloalkyl, —R⁹—CN, —R⁹—OR⁵,—R⁹—N(R⁴)R⁵, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; or R⁶ and R⁷, togetherwith the nitrogen to which they are attached, form a heterocyclyl orheteroaryl; and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groupfor R⁶ and R⁷ may be optionally substituted by one or more substituentsselected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl,halo, haloalkyl, —R⁸—CN, —R⁸—OR⁵, heterocyclyl and heteroaryl; or R¹ isaralkyl optionally substituted by one or more substituents selected fromthe group consisting of —R⁸—OR⁵, —C(O)OR⁵, halo, haloalkyl, alkyl,nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl; or R¹ is—R⁹—N(R¹⁰)R¹¹, —R⁹—N(R¹²)C(O)R¹¹ or —R⁹—N(R¹⁰)C(O)N(R¹⁰)R¹¹ where: eachR¹⁰ is hydrogen, alkyl, aryl, aralkyl or heteroaryl; each R¹¹ ishydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,—R⁹—OC(O)R⁵, —R⁹—C(O)OR⁵, —R⁹—C(O)N(R⁴)R⁵, —R⁹—C(O)R⁵, —R⁹—N(R⁴)R⁵,—R⁹—OR⁵, or —R⁹—CN; and R¹² is hydrogen, alkyl, aryl, aralkyl or—C(O)R⁵; and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groupfor R¹⁰ and R¹¹ may be optionally substituted by one or moresubstituents selected from the group consisting of alkyl, cycloalkyl,aryl, aralkyl, halo, haloalkyl, nitro, —R⁸—CN, —R⁸—OR⁵, —R⁸—C(O)R⁵,heterocyclyl and heteroaryl; or R¹ is heterocyclylalkyl orheteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl groupis optionally substituted by one or more substituents selected from thegroup consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, —R⁸—N(R⁴)R⁵,—R⁸—C(O)N(R⁴)R⁵, —R⁸—N(R⁵)C(O)R⁴, —R⁸—S(O)_(m)R⁴ (where m is 0, 1 or 2),—R⁸—CN, or —R⁸—NO₂; R^(2a), R^(2b), R^(2c) and R^(2d) are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,—R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃, —R⁸—C(O)R⁴,—C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴, —R⁸—C(O)N(R⁴)R⁵,—C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴, —N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴,—N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵, —N(R⁵)S(O)_(n)R⁴,—N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵, —N(R⁵)C(═NR⁵)N(R⁴)R⁵, and—N(R⁵)C(═N—CN)N(R⁴)R⁵, wherein each m is independently 0, 1, or 2 andeach n is independently 1 or 2; and wherein each of the cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R^(2a),R^(2b), R^(2c) and R^(2d) may be optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN, —R⁸—NO₂,—R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —S(O)_(m)R⁴, —R⁸—S(O)_(n)N(R⁴)R⁵, —R⁸—C(O)R⁴,—R⁸—C(O)OR⁴, —R⁸—C(O)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, and —N(R⁵)S(O)_(n)R⁴,wherein each m is independently 0, 1, or 2 and each n is independently 1or 2; or R^(2a) and R^(2b), together with the carbon ring atoms to whichthey are directly attached, may form a fused ring selected fromcycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2c) and R^(2d) areas defined above; or R^(2b) and R^(2c), together with the carbon ringatoms to which they are directly attached, may form a fused ringselected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and R^(2a)and R^(2d) are as defined above; or R^(2c) and R^(2d), together with thecarbon ring atoms to which they are directly attached, may form a fusedring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, andR^(2a) and R^(2b) are as defined above; R^(3a), R^(3b), R^(3c) andR^(3d) are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl,haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁸—CN,—R⁸—NO₂, —R⁸—OR⁵, —R⁸—N(R⁴)R⁵, —N═C(R⁴)R⁵, —S(O)_(m)R⁴, —OS(O)₂CF₃,—R⁸—C(O)R⁴, —C(S)R⁴, —C(R⁴)₂C(O)R⁵, —R⁸—C(O)OR⁴, —C(S)OR⁴,—R⁸—C(O)N(R⁴)R⁵, —C(S)N(R⁴)R⁵, —N(R⁵)C(O)R⁴, —N(R⁵)C(S)R⁴,—N(R⁵)C(O)OR⁴, —N(R⁵)C(S)OR⁴, —N(R⁵)C(O)N(R⁴)R⁵, —N(R⁵)C(S)N(R⁴)R⁵,—N(R⁵)S(O)_(n)R⁴, —N(R⁵)S(O)_(n)N(R⁴)R⁵, —R⁸—S(O)_(n)N(R⁴)R⁵,—N(R⁵)C(═NR⁵)N(R⁴)R⁵, and —N(R⁵)C(N═C(R⁴)R⁵)N(R⁴)R⁵, wherein each m isindependently 0, 1, or 2 and each n is independently 1 or 2; or R^(3a)and R^(3b), together with the carbon ring atoms to which they aredirectly attached, form a fused ring selected from cycloalkyl,heterocyclyl, aryl or heteroaryl, and R^(3c) and R^(3d) are as definedabove; or R^(3b) and R^(3c), together with the carbon ring atoms towhich they are directly attached, may form a fused ring selected fromcycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a) and R^(3d) areas defined above; or R^(3c) and R^(3d), together with the carbon ringatoms to which they are directly attached, may form a fused ringselected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and R^(3a)and R^(3b) are as defined above; each R⁴ and R⁵ is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; orwhen R⁴ and R⁵ are each attached to the same nitrogen atom, then R⁴ andR⁵, together with the nitrogen atom to which they are attached, may forma heterocyclyl or heteroaryl; each R⁸ is a direct bond or a straight orbranched alkylene chain, a straight or branched alkenylene chain or astraight or branched alkynylene chain; and each R⁹ is a straight orbranched alkylene chain, a straight or branched alkenylene chain or astraight or branched alkynylene chain.
 8. The compound of claim 7wherein: j is 0 and k is 1 or 2; Q is —C(O)— or —CF₂—; R¹ is hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl,heteroaryl, heterocyclyl, —R⁸—C(O)R⁵, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁴)R⁵,—S(O)₂—R⁵, —R⁹—S(O)_(m)—R⁵ (where m is 0, 1 or 2), —R⁸—OR⁵, —R⁸—CN,—R⁹—P(O)(OR⁵)₂, or —R⁹—O—R⁹—OR⁵; R^(2a), R^(2b), R^(2c) and R^(2d) areeach hydrogen; R^(2a), R^(2b), R^(2c) and R^(2d) are each hydrogen;R^(3a) and R^(3d) are each hydrogen; R^(3b) and R^(3c), together withthe carbon ring atoms to which they are directly attached, form a fusedring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; each R⁵is independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl and heteroaryl; each R⁸ is a direct bond ora straight or branched alkylene chain, a straight or branched alkenylenechain or a straight or branched alkynylene chain; and each R⁹ is astraight or branched alkylene chain, a straight or branched alkenylenechain or a straight or branched alkynylene chain.
 9. The compound ofclaim 8 wherein: j is 0 and k is 1 or 2; Q is —C(O)— or —CF₂—; R¹ ispentyl; R^(2a), R^(2b), R^(2c) and R^(3d) are each hydrogen; R^(3a) andR^(3d) are each hydrogen; and R^(3b) and R^(3c), together with thecarbon ring atoms to which they are directly attached, form a fuseddioxolyl ring.
 10. The compound of claim 9 selected from:1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione;1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dione;or8′,8′-difluoro-1-pentyl-7′,8′-dihydro-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxol]-2(1H)-one.11. A method of treating, preventing or ameliorating a disease or acondition in a mammal selected from the group consisting of pain,depression, cardiovascular diseases, respiratory diseases, andpsychiatric diseases, and combinations thereof, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of claim 1; as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof; or a pharmaceuticallyacceptable salt, solvate or prodrug thereof.
 12. The method of claim 11,wherein said disease or condition is selected from the group consistingof neuropathic pain, inflammatory pain, visceral pain, cancer pain,chemotherapy pain, trauma pain, surgical pain, post-surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,dental pain, chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,and combinations thereof.
 13. The method of claim 11, wherein saiddisease or condition is selected from the group consisting of painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, post-herpetic neuralgia, eudynia, heat sensitivity,tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associatedwith multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS),diabetic neuropathy, peripheral neuropathy, arthritic, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses, familialerythermalgia, primary erythermalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke or neural trauma, tachy-arrhythmias, atrialfibrillation and ventricular fibrillation.
 14. A method of treating painthrough inhibition of ion flux through a voltage-dependent sodiumchannel in a mammal, wherein the method comprises administering to themammal in need thereof a therapeutically effective amount of a compoundof claim 1; as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof; or a pharmaceutically acceptable salt, solvate or prodrugthereof.
 15. A method of decreasing ion flux through a voltage-dependentsodium channel in a cell in a mammal, wherein the method comprisescontacting the cell with a compound of claim 1; as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof; or a pharmaceuticallyacceptable salt, solvate or prodrug thereof.
 16. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of claim 1; as a stereoisomer, enantiomer, tautomer thereof ormixtures thereof; or a pharmaceutically acceptable salt, solvate orprodrug thereof.